JP2001513567A - Camptothecin analogs and methods for their preparation - Google Patents
Camptothecin analogs and methods for their preparationInfo
- Publication number
- JP2001513567A JP2001513567A JP2000507386A JP2000507386A JP2001513567A JP 2001513567 A JP2001513567 A JP 2001513567A JP 2000507386 A JP2000507386 A JP 2000507386A JP 2000507386 A JP2000507386 A JP 2000507386A JP 2001513567 A JP2001513567 A JP 2001513567A
- Authority
- JP
- Japan
- Prior art keywords
- group
- trimethylsilyl
- mmol
- compound according
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 40
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title description 50
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- -1 carbamoyloxy group Chemical group 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 125000003277 amino group Chemical group 0.000 claims abstract description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 19
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 4
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract 3
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- KWEDUNSJJZVRKR-UHFFFAOYSA-N carbononitridic azide Chemical compound [N-]=[N+]=NC#N KWEDUNSJJZVRKR-UHFFFAOYSA-N 0.000 claims 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- 108090000323 DNA Topoisomerases Proteins 0.000 abstract description 9
- 102000003915 DNA Topoisomerases Human genes 0.000 abstract description 9
- 230000001404 mediated effect Effects 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 230000007018 DNA scission Effects 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 abstract description 2
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 2
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 abstract 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 abstract 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- 229940127093 camptothecin Drugs 0.000 description 36
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 238000003818 flash chromatography Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 21
- 230000000259 anti-tumor effect Effects 0.000 description 18
- YEMFHJFNJPXYOE-UHFFFAOYSA-N 3-iodo-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1I YEMFHJFNJPXYOE-UHFFFAOYSA-N 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 12
- 239000003921 oil Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 9
- 229960004768 irinotecan Drugs 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 150000002596 lactones Chemical group 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- QWUJGOIESPJIMM-UHFFFAOYSA-N tert-butyl n-(4-isocyanophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C([N+]#[C-])C=C1 QWUJGOIESPJIMM-UHFFFAOYSA-N 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GWAKINQTPRXSAN-UHFFFAOYSA-N (2-fluoro-6-isocyanophenyl)-trimethylsilane Chemical compound C[Si](C)(C)C1=C(F)C=CC=C1[N+]#[C-] GWAKINQTPRXSAN-UHFFFAOYSA-N 0.000 description 3
- IREMQIOSTDEUMK-UHFFFAOYSA-N 3-fluoro-2-trimethylsilylbenzaldehyde Chemical compound C[Si](C)(C)C1=C(F)C=CC=C1C=O IREMQIOSTDEUMK-UHFFFAOYSA-N 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000006552 Lewis Lung Carcinoma Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000002527 isonitriles Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- ISUVTQPDPBJTCK-UHFFFAOYSA-N tert-butyl n-(2-fluoro-4-nitrophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C([N+]([O-])=O)C=C1F ISUVTQPDPBJTCK-UHFFFAOYSA-N 0.000 description 3
- PXWXREMWXXEOJN-UHFFFAOYSA-N (2-fluoro-6-isocyanatophenyl)-trimethylsilane Chemical compound C[Si](C)(C)C1=C(F)C=CC=C1N=C=O PXWXREMWXXEOJN-UHFFFAOYSA-N 0.000 description 2
- BWNVSJBQIIWWJE-UHFFFAOYSA-N (4-isocyanophenyl) acetate Chemical compound CC(=O)OC1=CC=C([N+]#[C-])C=C1 BWNVSJBQIIWWJE-UHFFFAOYSA-N 0.000 description 2
- MYRYEHQHXYLMED-UHFFFAOYSA-N (4-nitrophenyl) 4-piperidin-1-ylpiperidine-1-carboxylate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)N1CCC(N2CCCCC2)CC1 MYRYEHQHXYLMED-UHFFFAOYSA-N 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 2
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 description 2
- LETNCFZQCNCACQ-UHFFFAOYSA-N 2-fluoro-4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1F LETNCFZQCNCACQ-UHFFFAOYSA-N 0.000 description 2
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 208000006268 Sarcoma 180 Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000002784 cytotoxicity assay Methods 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 208000001608 teratocarcinoma Diseases 0.000 description 2
- WBYYPBQKOOBWAE-UHFFFAOYSA-N tert-butyl n-(4-amino-2-fluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(N)C=C1F WBYYPBQKOOBWAE-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical compound CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 description 1
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
- ZGRXGZMRVZWOJO-UHFFFAOYSA-N 1,2-difluoro-3-isocyanobenzene Chemical compound FC1=CC=CC([N+]#[C-])=C1F ZGRXGZMRVZWOJO-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- OSBLTNPMIGYQGY-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;boric acid Chemical compound OB(O)O.OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O OSBLTNPMIGYQGY-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- WAZSVCKLDOMJJX-UHFFFAOYSA-N 2h-pyrrolo[3,4-b]quinoline Chemical compound C1=CC=CC2=CC3=CNC=C3N=C21 WAZSVCKLDOMJJX-UHFFFAOYSA-N 0.000 description 1
- HZSGANARGPIXQM-UHFFFAOYSA-N 3-bromoprop-1-ynyl(triethyl)silane Chemical compound CC[Si](CC)(CC)C#CCBr HZSGANARGPIXQM-UHFFFAOYSA-N 0.000 description 1
- CSXPORFIUHLWJC-UHFFFAOYSA-N 3-bromoprop-1-ynyl-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)C#CCBr CSXPORFIUHLWJC-UHFFFAOYSA-N 0.000 description 1
- BASFFFHJDLRLDO-UHFFFAOYSA-N 3-bromoprop-1-ynyl-tert-butyl-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C#CCBr)(C(C)(C)C)C1=CC=CC=C1 BASFFFHJDLRLDO-UHFFFAOYSA-N 0.000 description 1
- IEDKWVCTWQYKRK-UHFFFAOYSA-N 3-bromoprop-1-ynyl-tri(propan-2-yl)silane Chemical compound CC(C)[Si](C(C)C)(C(C)C)C#CCBr IEDKWVCTWQYKRK-UHFFFAOYSA-N 0.000 description 1
- LWBSPERSKODZRR-UHFFFAOYSA-N 3-bromoprop-1-ynylsilane Chemical compound [SiH3]C#CCBr LWBSPERSKODZRR-UHFFFAOYSA-N 0.000 description 1
- RUVHEBACQXILNY-UHFFFAOYSA-N 3-fluoro-2-trimethylsilylbenzoic acid Chemical compound C[Si](C)(C)C1=C(F)C=CC=C1C(O)=O RUVHEBACQXILNY-UHFFFAOYSA-N 0.000 description 1
- PIKNVEVCWAAOMJ-UHFFFAOYSA-N 3-fluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1 PIKNVEVCWAAOMJ-UHFFFAOYSA-N 0.000 description 1
- LEAKQIXYSHIHCW-UHFFFAOYSA-N 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine Chemical compound N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CN1 LEAKQIXYSHIHCW-UHFFFAOYSA-N 0.000 description 1
- USVZHTBPMMSRHY-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-chlorophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Cl USVZHTBPMMSRHY-UHFFFAOYSA-N 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- DAUURUHVYWJQHD-UHFFFAOYSA-N C1C2([SiH2]C#CCBr)C(C)(C)C1CCC2 Chemical compound C1C2([SiH2]C#CCBr)C(C)(C)C1CCC2 DAUURUHVYWJQHD-UHFFFAOYSA-N 0.000 description 1
- 101000679711 Caenorhabditis elegans DNA topoisomerase 1 Proteins 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108020004638 Circular DNA Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- HMACVVLBFDMSNA-UHFFFAOYSA-N ClCCCC(C#C[SiH](C)C)Br Chemical compound ClCCCC(C#C[SiH](C)C)Br HMACVVLBFDMSNA-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 1
- 101000879758 Homo sapiens Sjoegren syndrome nuclear autoantigen 1 Proteins 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 241001420622 Meris Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100037330 Sjoegren syndrome nuclear autoantigen 1 Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000008051 TBE buffer Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- LFWYILMPCMPPPH-UHFFFAOYSA-N carbamic acid;1-pyrrolidin-1-ylpyrrolidine Chemical compound NC(O)=O.C1CCCN1N1CCCC1 LFWYILMPCMPPPH-UHFFFAOYSA-N 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 description 1
- 102000054896 human PML Human genes 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N isonitrile group Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- SXQCTESRRZBPHJ-UHFFFAOYSA-M lissamine rhodamine Chemical compound [Na+].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O SXQCTESRRZBPHJ-UHFFFAOYSA-M 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- ORIWMYRMOGIXGG-ZXVJYWQYSA-N lurtotecan dihydrochloride Chemical compound Cl.Cl.O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 ORIWMYRMOGIXGG-ZXVJYWQYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 238000007122 ortho-metalation reaction Methods 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- RCIBIGQXGCBBCT-UHFFFAOYSA-N phenyl isocyanide Chemical compound [C-]#[N+]C1=CC=CC=C1 RCIBIGQXGCBBCT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- PYYHPFRGSSTZMC-UHFFFAOYSA-N tert-butyl n-(2-fluoro-4-isocyanophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C([N+]#[C-])C=C1F PYYHPFRGSSTZMC-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BOJSDHZZKKYWAS-UHFFFAOYSA-N tetrakis(trimethylsilyl)silane Chemical compound C[Si](C)(C)[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C BOJSDHZZKKYWAS-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【０００１】 （技術分野） この出願は米国特許出願第08/436,799号（これは米国特許出願第08/085,190号
の一部継続出願である）の一部継続出願であり、これらの開示が参考として本明
細書に含まれる。 本発明は新規化合物及びこれらの調製方法、特にシリルカンプトテシン誘導体
又は類似体及びこのようなシリルカンプトテシン類似体の調製方法に関する。TECHNICAL FIELD This application is a continuation-in-part of US patent application Ser. No. 08 / 436,799, which is a continuation-in-part of US patent application Ser. No. 08 / 085,190, the disclosure of which is incorporated by reference. As included herein. The present invention relates to novel compounds and methods for their preparation, particularly silyl camptothecin derivatives or analogs, and methods for preparing such silyl camptothecin analogs.
【０００２】 （背景技術） (20S)-カンプトテシン（CPT、以下を参照のこと）及びその誘導体は化学療法 による充実性腫瘍の治療に最も有望な薬剤の幾つかである。例えば、Wall, M. E
.ら, J. Ethnopharmacol., 51, 239 (1996); Camptothecin: New Anticancer Ag
ents; Potmesil, M.及びPinedo, H.編集; CRC, Boca Raton, FL (1995); Bonnet
erre, J., Bull. Canc., 82, 623 (1995); Sinha, D. K., Drugs, 49, 11 (1995
)を参照のこと。この天然アルカロイドは1966年にWallにより中国の植物であるC
amptotheca accuminataのエキスから最初に単離された(Wall, M. E.ら, J. Am.
Chem. Soc., 88, 3888 (1966))。以下に示されるように、カンプトテシンは一般
に2-ピリドン環（環Ｄ）（これは順にラクトン環（環Ｅ）に縮合されている）に
縮合されているピロロ〔3,4-b〕キノリン系（環ABC）を含む縮合環系を有する。BACKGROUND OF THE INVENTION (20S) -Camptothecin (CPT, see below) and its derivatives are some of the most promising drugs for the treatment of solid tumors by chemotherapy. For example, Wall, ME
. Et al., J. Ethnopharmacol., 51, 239 (1996); Camptothecin: New Anticancer Ag
ents; Potmesil, M. and Pinedo, H. Edit; CRC, Boca Raton, FL (1995); Bonnet
erre, J., Bull.Canc., 82, 623 (1995); Sinha, DK, Drugs, 49, 11 (1995).
)checking. This natural alkaloid was a Chinese plant C by Wall in 1966.
First isolated from extracts of amptotheca accuminata (Wall, ME et al., J. Am.
Chem. Soc., 88, 3888 (1966)). As shown below, camptothecin is generally a pyrrolo [3,4-b] quinoline system fused to a 2-pyridone ring (ring D), which is in turn fused to a lactone ring (ring E). Ring ABC).
【０００３】 [0003]
【０００４】 カンプトテシンはトポイソメラーゼＩ毒物のファミリーに属する。例えば、Fr
oelich-Ammon, S. J.ら, J. Biol. Chem., 270, 21429 (1995)を参照のこと。現
在までの研究はこの分子が細胞酵素トポイソメラーゼＩにより超らせんDNAの巻 戻しに干渉することにより作用することを強く示唆し、その酵素は通常悪性細胞
中で過剰発現される。高度に複製する癌細胞中で、これがアポトーシス及びプロ
グラムされた死滅をもたらすイベントのカスケードを誘発する。Slichenmyer, W
. J.ら, J. Natl. Cancer Inst., 85, 271 (1993)を参照のこと。分子薬理学レ ベルにおける最近の進歩がPommier, Y.ら, Proc. Natl. Acad. Sci. USA, 92, 8
861 (1995)に総説されている。 カンプトテシンの初期の臨床試験は生理学的適合性媒体中のその不充分な溶解
性により制限された。更に、ラクトン環を水酸化ナトリウムで開環することによ
りカンプトテシンの水溶性ナトリウム塩を生成しようとする早期の試みは不充分
な抗腫瘍活性を有する化合物をもたらした。その後に、閉環されたラクトン形態
が抗腫瘍活性の絶対必要条件であることが報告された。Wani, M. C.ら, J. Med.
Chem., 23, 554 (1980)を参照のこと。更に最近、構造−活性研究が更に良好な
溶解性及び更に良好な抗腫瘍活性を有する類似化合物を同定していた。例えば、
トポテカン(TPT)及びイリノテカン(IRT)が最近米国において販売について認可さ
れており、一方、GI-147211Cが後期臨床試験中である。これらの類似体は種々の
治療し難い充実性腫瘍、例えば、悪性メラノーマ、胃癌、乳癌、卵巣癌、肺癌及
び結腸直腸癌に対し有効であり、徐々に***する癌系の治療に特に有望と思われ
る。例えば、Kingsbury, W. D.ら, J. Med. Chem., 34, 98 (1991); Sawada, S.
ら, Chem. Pharm. Bull., 39, 1446 (1991); Luzzio, M. J.ら, J. Med. Chem.,
38, 395 (1995); Abigerges, D.ら, J. Clin. Oncol., 13, 210 (1995)を参照 のこと。更に、相乗効果又は累積的効果がシスプラチン、放射線、又は温熱療法
との組み合わせ療法で観察されていた。Fukuda, M.ら, Canc. Res., 56, 789 (1
996); Goldwasser, F.ら, Clin. Canc. Res., 2, 687 (1996); Wang, D. S.ら,
Biol. Pharm. Bull., 19, 354 (1996)を参照のこと。[0004] Camptothecin belongs to the family of topoisomerase I toxicants. For example, Fr
See oelich-Ammon, SJ et al., J. Biol. Chem., 270, 21429 (1995). Studies to date strongly suggest that this molecule acts by interfering with the unwinding of supercoiled DNA by the cellular enzyme topoisomerase I, which is usually overexpressed in malignant cells. In highly replicating cancer cells, this triggers a cascade of events leading to apoptosis and programmed death. Slichenmyer, W
See J. et al., J. Natl. Cancer Inst., 85, 271 (1993). Recent advances in the molecular pharmacology level have been reported by Pommier, Y. et al., Proc. Natl. Acad. Sci. USA, 92, 8
861 (1995). Early clinical trials of camptothecin were limited by its poor solubility in physiologically compatible media. Furthermore, early attempts to generate the water-soluble sodium salt of camptothecin by opening the lactone ring with sodium hydroxide have resulted in compounds with insufficient antitumor activity. It was subsequently reported that the closed lactone form was an absolute prerequisite for antitumor activity. Wani, MC et al., J. Med.
Chem., 23, 554 (1980). More recently, structure-activity studies have identified analogous compounds with better solubility and better antitumor activity. For example,
Topotecan (TPT) and irinotecan (IRT) have recently been approved for sale in the United States, while GI-147211C is in late clinical trials. These analogs are effective against a variety of hard-to-treat solid tumors, such as malignant melanoma, gastric, breast, ovarian, lung and colorectal cancers, and may be particularly promising for the treatment of gradually dividing cancer systems. It is. See, for example, Kingsbury, WD et al., J. Med. Chem., 34, 98 (1991); Sawada, S.
Chem. Pharm. Bull., 39, 1446 (1991); Luzzio, MJ et al., J. Med. Chem.,
38, 395 (1995); Abigerges, D. et al., J. Clin. Oncol., 13, 210 (1995). Furthermore, synergistic or cumulative effects have been observed with combination therapy with cisplatin, radiation, or hyperthermia. Fukuda, M. et al., Canc. Res., 56, 789 (1
996); Goldwasser, F. et al., Clin.Canc. Res., 2, 687 (1996); Wang, DS et al.,
See Biol. Pharm. Bull., 19, 354 (1996).
【０００５】 殆どの研究がカンプトテシンの水溶性誘導体の開発に集中していたが、新規製
剤化、例えば、脂質−複合体形成、リポソーム封入、及び湿式混錬技術が最近開
発されていた。このような製剤化は不充分に水溶性のカンプトテシンに新しい治
療機会をもたらす。Daoud, S. S.ら, Anti-Cancer Drugs, 6, 83 (1995); Meris
ko-Liversidge, E.ら, Pharm. Res., 13, 272 (1996); 及びPantazis, P., Leuk
emia Res., 19, 775 (1995)を参照のこと。これらの製剤化の魅力的な特徴は薬 物生体分布に関するそれらの影響である。Sugarman及び共同研究者らは遊離カン
プトテシンが肺の柔組織中で最大濃度に達するが、脂質−複合体形成されたカン
プトテシンが胃腸道中で最高濃度を有することを最近報告していた。これらの結
果は結腸癌の治療に新しくかつ重要な見通しを開く。Sugarman, S. M.ら, Canc.
Chemother. Pharmacol., 37, 531 (1996)を参照のこと。不溶性カンプトテシン
類似体を使用することの別の重要な局面はそれらがそれらの水溶性同種物よりも
通常活性であり、薬物誘発耐性を生じそうにないことである。何とならば、おそ
らくそれらがp-糖タンパク質多薬物トランスポーターの基質ではないからである
。Pantazis, P., Clin. Canc. Res., 1, 1235 (1995)を参照のこと。 この状況下で、良好乃至優れた抗腫瘍活性と異なる溶解性及び生体分布プロフ
ィールとを併有する新規カンプトテシン類似体が種々の型の癌の治療の治療集積
に重要な役割を果たし得る。 カンプトテシン及びその類似体の判明した有益な生物活性を考えると、付加的
なカンプトテシン類似体及びカンプトテシン類似体の調製方法を開発することが
望ましい。While most research has focused on the development of water-soluble derivatives of camptothecin, new formulations, such as lipid-complex formation, liposome encapsulation, and wet-mixing techniques have recently been developed. Such a formulation provides a new therapeutic opportunity for poorly water soluble camptothecin. Daoud, SS et al., Anti-Cancer Drugs, 6, 83 (1995); Meris
ko-Liversidge, E. et al., Pharm. Res., 13, 272 (1996); and Pantazis, P., Leuk.
emia Res., 19, 775 (1995). An attractive feature of these formulations is their effect on drug biodistribution. Sugarman and co-workers have recently reported that free camptothecin reaches a maximum concentration in parenchyma of the lung, whereas lipid-complexed camptothecin has the highest concentration in the gastrointestinal tract. These results open new and important prospects for the treatment of colon cancer. Sugarman, SM et al., Canc.
Chemother. Pharmacol., 37, 531 (1996). Another important aspect of using insoluble camptothecin analogs is that they are usually more active than their water-soluble analogs and are unlikely to give rise to drug-induced resistance. Perhaps because they are not substrates for the p-glycoprotein multidrug transporter. See Pantazis, P., Clin. Canc. Res., 1, 1235 (1995). In this context, novel camptothecin analogs that combine good to excellent anti-tumor activity with different solubility and biodistribution profiles may play an important role in the therapeutic integration of the treatment of various types of cancer. Given the found beneficial biological activity of camptothecin and its analogs, it is desirable to develop additional camptothecin analogs and methods of preparing camptothecin analogs.
【０００６】 （発明の開示） 本発明は一般に下記の式(1)：DISCLOSURE OF THE INVENTION The present invention generally provides the following formula (1):
【０００７】 [0007]
【０００８】 を有する化合物を提供する。 R1及びR2は独立に同じであり、又は異なり、好ましくは水素、アルキル基、ア
ルケニル基、アルキニル基、アルコキシル基、アリールオキシ基、アシルオキシ
基、カルボニルオキシ基、カルバモイルオキシ基、ハロゲン、ヒドロキシル基、
ニトロ基、シアノ基、アジド基、ホルミル基、ヒドラジノ基、アシル基、アミノ
基、-SRc（式中、Rcは水素、アシル基、アルキル基、又はアリール基である）で
あり、又はR1及びR2は一緒になって式-O(CH2)nO-（式中、ｎは整数１又は２を表
す）の基を形成する。 R3は好ましくはＨ、ハロゲン、ニトロ基、アミノ基、ヒドロキシル基、又はシ
アノ基である。また、R2及びR3は一緒になって式-O(CH2)nO-（式中、ｎは整数１
又は２を表す）の基を形成することができる。 R4は好ましくはＨ、Ｆ、C1-3アルキル基、C2-3アルケニル基、C2-3アルキニル
基、又はC1-3アルコキシル基である。 R5はC1-10アルキル基であることが好ましい。好ましいアルキル基はエチル基 である。R5に好ましい置換アルキル基として、アリル基、プロパルギル基及びベ
ンジル基が挙げられる。 R6、R7及びR8は好ましくは独立に（同じであり、又は異なり）C1-10アルキル 基、C2-10アルケニル基、C2-10アルキニル基又はアリール基である。R6、R7及び
R8に好ましい置換アルキル基は-(CH2)NR9基（式中、Ｎは１〜10の範囲内の整数 であり、かつR9はヒドロキシル基、アルコキシル基、アミノ基、ハロゲン原子、
シアノ基又はニトロ基である）である。R9に好ましいアミノ基として、アルキル
アミノ基及びジアルキルアミノ基が挙げられる。There is provided a compound having the formula: R 1 and R 2 are independently the same or different, preferably hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, a carbonyloxy group, a carbamoyloxy group, a halogen, a hydroxyl group ,
A nitro group, a cyano group, an azide group, a formyl group, a hydrazino group, an acyl group, an amino group, -SR c (where R c is hydrogen, an acyl group, an alkyl group, or an aryl group), or R 1 and R 2 together form a group of the formula —O (CH 2 ) n O—, where n represents an integer 1 or 2. R 3 is preferably H, halogen, nitro, amino, hydroxyl, or cyano. R 2 and R 3 together form a formula —O (CH 2 ) n O— (where n is an integer 1
Or 2) can be formed. R 4 is preferably H, F, a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, or a C 1-3 alkoxyl group. R 5 is preferably a C 1-10 alkyl group. A preferred alkyl group is an ethyl group. Preferred substituted alkyl groups in R 5, an allyl group, and a propargyl group and benzyl group. R 6 , R 7 and R 8 are preferably independently (same or different) C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or aryl. R 6 , R 7 and
A preferred substituted alkyl group for R 8 is — (CH 2 ) N R 9 group, wherein N is an integer in the range of 1 to 10, and R 9 is a hydroxyl group, an alkoxyl group, an amino group, a halogen atom,
A cyano group or a nitro group). Preferred amino groups for R 9 include an alkylamino group and a dialkylamino group.
【０００９】 “アルキル”、“アリール”という用語及びその他の基は特にことわらない限
り未置換基及び置換基の両方を一般に表す。特にことわらない限り、アルキル基
はC1-C15（即ち、１〜15個の炭素原子を有する）アルキル基であることが好まし
く、C1-C10アルキル基であることが更に好ましく、分岐又は非分岐の非環式又は
環式であってもよい。アルキル基の上記定義及びその他の定義はまたその基が別
の基の置換基（例えば、アルキルアミノ基又はジアルキルアミノ基の置換基とし
てのアルキル基）である場合にも適用される。“アリール”という用語はフェニ
ル又はナフチルを表す。本明細書に使用される“ハロゲン”又は“ハロ”という
用語はフルオロ、クロロ、ブロモ及びヨードを表す。 “アルコキシル”という用語は-ORd（式中、Rdはアルキル基である）を表す。
“アリールオキシ”という用語は-ORe（式中、Reはアリール基である）を表す。
アシルという用語は-OCRfを表す。“アルケニル”という用語は好ましくは2-15 個の炭素原子、更に好ましくは3-10個の炭素原子を有する不飽和基(-C=CHRg)を 表す。“アルキニル”という用語は好ましくは2-15個の炭素原子、更に好ましく
は3-10個の炭素原子を有する不飽和基(-C≡CRh)を表す。The terms “alkyl”, “aryl” and other groups generally refer to both unsubstituted and substituted groups unless otherwise indicated. Unless otherwise stated, the alkyl group is preferably a C 1 -C 15 (ie, having 1 to 15 carbon atoms) alkyl group, more preferably a C 1 -C 10 alkyl group, Alternatively, it may be unbranched acyclic or cyclic. The above and other definitions of an alkyl group also apply when the group is a substituent on another group (eg, an alkyl group as a substituent on an alkylamino or dialkylamino group). The term "aryl" represents phenyl or naphthyl. The terms "halogen" or "halo" as used herein refer to fluoro, chloro, bromo and iodo. The term “alkoxyl” refers to —OR d , where R d is an alkyl group.
The term “aryloxy” refers to —OR e , where R e is an aryl group.
The term acyl represents -OCR f . The term "alkenyl" refers to an unsaturated group, preferably having 2-15 carbon atoms, more preferably 3-10 carbon atoms (-C = CHR g ). The term “alkynyl” refers to an unsaturated group (—C≡CR h ), preferably having 2-15 carbon atoms, more preferably 3-10 carbon atoms.
【００１０】 先に示された基は、活性を保持するカンプトテシン類似体を合成するための種
々の置換基で置換し得る。例えば、アルキル基はベンジル基、フェニル基、アル
コキシル基、ヒドロキシル基、アミノ基（例えば、遊離アミノ基、アルキルアミ
ノ基、ジアルキルアミノ基及びアリールアミノ基を含む）、アルケニル基、アル
キニル基及びアシルオキシ基を含むが、これらに限定されない一つ以上の基で置
換されることが好ましいかもしれない。アミノ基(-NRaRb)の場合、Ra及びRbは独
立に水素、アシル基、アルキル基、又はアリール基であることが好ましい。アシ
ル基はアルキル基、ハロアルキル基（例えば、ペルフルオロアルキル基）、アル
コキシル基、アミノ基及びヒドロキシル基で置換されることが好ましく、即ち、
Rfがこれらの置換基であることが好ましい。アルキニル基及びアルケニル基はア
ルキル基、アルコキシアルキル基、アミノアルキル基及びベンジル基を含むが、
これらに限定されない一つ以上の基で置換されることが好ましく、即ち、Rg及び
Rhがこれらの置換基であることが好ましい。The groups set forth above can be substituted with various substituents to synthesize camptothecin analogs that retain activity. For example, an alkyl group includes a benzyl group, a phenyl group, an alkoxyl group, a hydroxyl group, an amino group (including, for example, a free amino group, an alkylamino group, a dialkylamino group and an arylamino group), an alkenyl group, an alkynyl group and an acyloxy group. It may be preferable to be substituted with one or more groups, including but not limited to. In the case of an amino group (—NR a R b ), Ra and R b are preferably independently hydrogen, an acyl group, an alkyl group, or an aryl group. The acyl group is preferably substituted with an alkyl group, a haloalkyl group (for example, a perfluoroalkyl group), an alkoxyl group, an amino group and a hydroxyl group,
It is preferred that R f is one of these substituents. Alkynyl and alkenyl groups include alkyl, alkoxyalkyl, aminoalkyl and benzyl groups,
Preferably, it is substituted with one or more groups, but not limited thereto, i.e., R g and
Preferably, R h is one of these substituents.
【００１１】 本明細書に使用される“アシルオキシ”という用語は基As used herein, the term “acyloxy” refers to the group
【００１２】 [0012]
【００１３】 を表す。 本明細書に使用される“カルボニルオキシ”という用語は基Represents As used herein, the term "carbonyloxy" refers to the group
【００１４】 [0014]
【００１５】 を表す。 本明細書に使用される“カルバモイルオキシ”という用語は基[0015] The term "carbamoyloxy" as used herein refers to the group
【００１６】 [0016]
【００１７】 を表す。 アミノ基及びヒドロキシル基は当業界で知られているような保護基を含んでい
てもよい。アミノ基に好ましい保護基として、tert-ブチルオキシカルボニル、 ホルミル、アセチル、ベンジル、p-メトキシベンジルオキシカルボニル、トリチ
ルが挙げられる。当業者に知られているようなその他の好適な保護基がGreen, T
., Wuts, P.G.M., Protective Groups in Organic Synthesis, Wiley (1991)に 開示されており、その開示が参考として本明細書に含まれる。 一般に、R1、R2、R3、R6、R7及びR8は得られるカンプトテシン類似体の活性を
維持するために過度に嵩高ではないことが好ましい。それ故、R1、R2、R3、R6、
R7及びR8は独立に約250未満の分子量を有することが好ましい。R1、R2、R3、R6 、R7及びR8は約200未満の分子量を有することが更に好ましい。 本発明のカンプトテシン類似体の幾つかは無機酸との塩、例えば、塩酸塩、臭
化水素酸塩、硫酸塩、リン酸塩、及び硝酸塩（これらに限定されない）として医
薬上の使用のために調製し得る。また、カンプトテシン類似体は有機酸との塩、
例えば、酢酸塩、酒石酸塩、フマル酸塩、コハク酸塩、クエン酸塩、メタンスル
ホン酸塩、p-トルエンスルホン酸塩、及びステアリン酸塩（これらに限定されな
い）として調製し得る。その他の酸は本発明の化合物及びそれらの医薬上許され
る塩の調製において中間体として使用し得る。Represents The amino and hydroxyl groups may contain protecting groups as known in the art. Preferred protecting groups for the amino group include tert-butyloxycarbonyl, formyl, acetyl, benzyl, p-methoxybenzyloxycarbonyl, and trityl. Other suitable protecting groups as known to those skilled in the art are described in Green, T
, Wuts, PGM, Protective Groups in Organic Synthesis, Wiley (1991), the disclosure of which is incorporated herein by reference. In general, it is preferred that R 1 , R 2 , R 3 , R 6 , R 7 and R 8 are not excessively bulky to maintain the activity of the resulting camptothecin analog. Therefore, R 1 , R 2 , R 3 , R 6 ,
Preferably, R 7 and R 8 independently have a molecular weight of less than about 250. More preferably, R 1 , R 2 , R 3 , R 6 , R 7 and R 8 have a molecular weight of less than about 200. Some of the camptothecin analogs of the present invention are for pharmaceutical use as salts with inorganic acids, such as, but not limited to, hydrochlorides, hydrobromides, sulfates, phosphates, and nitrates. Can be prepared. Camptothecin analogs are also salts with organic acids,
For example, it may be prepared as, but not limited to, acetate, tartrate, fumarate, succinate, citrate, methanesulfonate, p-toluenesulfonate, and stearate. Other acids may be used as intermediates in the preparation of the compounds of the present invention and their pharmaceutically acceptable salts.
【００１８】 精製目的のために、Ｅ環（ラクトン環）はアルカリ金属、例えば、水酸化ナト
リウム又は水酸化カルシウム（これらに限定されない）で開環されて式(1)の化 合物の開環されたＥ環類似体を生成してもよい。こうして得られた中間体は水中
で更に可溶性であり、精製されて、酸による処理後に、本発明のカンプトテシン
類似体の精製形態を生成してもよい。 また、Ｅ環は修飾されて水又はその他の溶媒中の異なる溶解性プロフィールを
有する式(1)の化合物の類似体を生成してもよい。この目標を達成するための方 法として、水溶性アミノ基によるＥ環の開環又は水溶性基、例えば、ポリエチレ
ングリコール基によるＥ環の位置20におけるヒドロキシル基の官能化が挙げられ
るが、これらに限定されない。こうして調製された類似体はプロドラッグとして
作用する。換言すれば、これらの類似体は生きている生物に投与された時に式(1
)の化合物（閉環されたＥ環構造を有する）を再生する。Greenwald, R.B.ら, J.
Med. Chem., 39, 1938 (1996)を参照のこと。For purification purposes, ring E (lactone ring) is opened with an alkali metal, such as, but not limited to, sodium hydroxide or calcium hydroxide to open the compound of formula (1). E-ring analogs may be produced. The intermediate thus obtained is more soluble in water and may be purified to yield, after treatment with an acid, a purified form of the camptothecin analog of the invention. Ring E may also be modified to produce analogs of compounds of formula (1) having different solubility profiles in water or other solvents. Methods to achieve this goal include opening of the E-ring with a water-soluble amino group or functionalization of the hydroxyl group at position 20 of the E-ring with a water-soluble group, for example, a polyethylene glycol group. Not limited. The analog thus prepared acts as a prodrug. In other words, these analogs when administered to living organisms have the formula (1
) Is regenerated (having a closed E-ring structure). Greenwald, RB et al., J.
See Med. Chem., 39, 1938 (1996).
【００１９】 また、本発明は医薬有効量の式(1)の化合物又はその医薬上許される塩を投与 することを特徴とする患者の治療方法を提供する。化合物は、例えば、静脈内、
筋肉内、経口、皮下、腫瘍内、皮内、及び非経口を含むが、これらに限定されな
い投与のあらゆる通常の経路により癌及び／又は白血病で冒された患者に投与さ
れてもよい。医薬有効量又は投与量は体重1kg当り式(1)の化合物0.01〜60mgであ
ることが好ましい。医薬有効量又は投与量は体重1kg当り式(1)の化合物0.1〜40m
gであることが更に好ましい。一般に、医薬有効量又は投与量は抗白血病挙動及 び／または抗腫瘍（抗癌）挙動を示すのに有効な式(1)の化合物の量を含む。医 薬上許される担体又は希釈剤と混在して活性成分として式(1)の化合物又はその 医薬上許される塩を含む医薬組成物がまた本発明の範囲内にある。 また、本発明は式(1)の化合物のいずれかと医薬上許される担体とを含む医薬 組成物を提供する。組成物は式(1)の化合物0.1mg〜500mgを含んでもよく、また 投与の様式に適したあらゆる形態に構成されてもよい。The present invention also provides a method for treating a patient, comprising administering a pharmaceutically effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof. The compound can be administered, for example, intravenously,
It may be administered to a patient affected by cancer and / or leukemia by any of the usual routes of administration including, but not limited to, intramuscular, oral, subcutaneous, intratumoral, intradermal, and parenteral. The pharmaceutically effective amount or dose is preferably 0.01 to 60 mg of the compound of the formula (1) per kg of body weight. A pharmaceutically effective amount or dose is 0.1 to 40 m of the compound of formula (1) per kg of body weight.
It is more preferably g. Generally, a pharmaceutically effective amount or dosage comprises an amount of a compound of formula (1) effective to exhibit anti-leukemic and / or anti-tumor (anti-cancer) behavior. Pharmaceutical compositions containing a compound of Formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with a pharmaceutically acceptable carrier or diluent are also within the scope of the invention. The present invention also provides a pharmaceutical composition comprising any of the compounds of formula (1) and a pharmaceutically acceptable carrier. The compositions may contain from 0.1 mg to 500 mg of the compound of formula (1) and may be made up in any form suitable for the mode of administration.
【００２０】 （発明を実施するための最良の形態） 化合物 式(1)の化合物の中で、Ｅ環の位置20に(S)配置を有する化合物が医薬上の使用
に好ましい。 R1及びR2が独立に（同じであり、又は異なり）Ｈ、ヒドロキシル基、ハロ基、
アミノ基、ニトロ基、シアノ基、C1-3アルキル基、C1-3ペルハロアルキル基、C1 -3 アルケニル基、C1-3アルキニル基、C1-3アルコキシル基、C1-3アミノアルキル
基、C1-3アルキルアミノ基、C1-3ジアルキルアミノ基であることが好ましく、又
はR1及びR2が一緒になって式-O(CH2)nO-（式中、ｎは整数１又は２を表す）の基
を形成する。R1及びR2が独立に（同じであり、又は異なり）Ｈ、メチル基、アミ
ノ基、ニトロ基、シアノ基、ヒドロキシル基、ヒドロキシメチル基、メチルアミ
ノ基、ジメチルアミノ基、エチルアミノ基、ジエチルアミノ基、アミノメチル基
、メチルアミノメチル基、ジメチルアミノメチル基、等であることが更に好まし
い。 R3がＦ、アミノ基、又はヒドロキシル基であることが好ましい。R4がＨ又はＦ
であることが好ましい。R5がエチル基であることが好ましい。R6、R7及びR8が独
立に（同じであり、又は異なり）C1-6アルキル基、フェニル基又は-(CH2)NR10基
（式中、Ｎは１〜６の範囲内の整数であり、かつR10はハロゲン又はシアノ基で ある）であることが好ましい。BEST MODE FOR CARRYING OUT THE INVENTION Compounds Among the compounds of formula (1), compounds having the (S) configuration at position 20 of the E ring are preferred for pharmaceutical use. R 1 and R 2 are independently (same or different) H, hydroxyl group, halo group,
An amino group, a nitro group, a cyano group, C 1-3 alkyl, C 1-3 perhaloalkyl group, C 1 -3 alkenyl group, C 1-3 alkynyl group, C 1-3 alkoxyl group, C 1-3 amino It is preferably an alkyl group, a C 1-3 alkylamino group, a C 1-3 dialkylamino group, or R 1 and R 2 together form a formula —O (CH 2 ) n O— Represents an integer 1 or 2). R 1 and R 2 are independently (same or different) H, methyl, amino, nitro, cyano, hydroxyl, hydroxymethyl, methylamino, dimethylamino, ethylamino, diethylamino More preferably, it is a group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, or the like. Preferably, R 3 is F, an amino group, or a hydroxyl group. R 4 is H or F
It is preferred that Preferably, R 5 is an ethyl group. R 6 , R 7 and R 8 are independently (same or different) C 1-6 alkyl group, phenyl group or — (CH 2 ) N R 10 group (wherein N is in the range of 1 to 6) And R 10 is a halogen or cyano group).
【００２１】 調製の方法 本発明の化合物は図１に示された一般の合成スキームに従って調製し得る。図
１の合成スキームにおいて、ヨードピリドン２が最初にプロパルギル誘導体でN-
アルキル化されて遊離基前駆体４を生じる。次いで遊離基前駆体４がアリールイ
ソニトリル５で遊離基カスケードを受けて生成物１を生じる。N-アルキル化は最
適化条件に従って円滑に進行する。Curran, D.P.ら, Tetrahedron Lett., 36, 8
917 (1995)（その開示が参考として本明細書に含まれる）を参照のこと。ヨード
ピリドン２の合成及び遊離基カスケードの条件は既に報告されていた。プロパル
ギル化剤３は好適なシリル化剤R6R7R8SiXによるプロパルギルアルコールのジア ニオンの通常のシリル化、続いて脱離基、例えば、ブロミド、ヨージド又はスル
ホネートへのプロパルギルアルコールの変換により容易に調製される。Curran,
D.P.ら, Angew. Chem. Int. Ed. Engl., 34, 2683 (1995) （その開示が参考と して本明細書に含まれる）、及び1995年５月８日に出願された米国特許出願第08
,436,799号（その開示が参考として本明細書に含まれる）を参照のこと。Methods of Preparation The compounds of the present invention can be prepared according to the general synthetic scheme shown in FIG. In the synthetic scheme of FIG. 1, iodopyridone 2 is initially a propargyl derivative and N-
Alkylation to give the free radical precursor 4. The free radical precursor 4 then undergoes a free radical cascade with the arylisonitrile 5 to give the product 1. N-alkylation proceeds smoothly according to optimization conditions. Curran, DP et al., Tetrahedron Lett., 36, 8
917 (1995), the disclosure of which is incorporated herein by reference. The conditions for the synthesis of iodopyridone 2 and the free radical cascade have already been reported. Propargylating agent 3 is readily prepared by the conventional silylation of dianion of propargyl alcohol with a suitable silylating agent R 6 R 7 R 8 SiX, followed by conversion of the propargyl alcohol to a leaving group such as bromide, iodide or a sulfonate. Is prepared. Curran, ENG GB
DP et al., Angew. Chem. Int. Ed. Engl., 34, 2683 (1995), the disclosure of which is incorporated herein by reference, and US patent application filed May 8, 1995. 08th
No., 436,799, the disclosure of which is incorporated herein by reference.
【００２２】 一般に、ヘキサメチルスズ、ヘキサメチルジシラン、又はテトラキス（トリメ
チルシリル）シランを含むが、これらに限定されない種々の試薬が遊離基カスケ
ードに使用し得る。この反応のエネルギーの源は太陽灯又は紫外線灯であっても
よい。温度は約25℃〜150℃にセットされることが好ましい。温度は約70℃にセ ットされることが更に好ましい。一般に遊離基カスケードに不活性であること以
外に、使用される溶媒の選択に制限はない。好ましい溶媒として、ベンゼン、ト
ルエン、アセトニトリル、THF及びtert-ブタノールが挙げられる。また、反応条
件の温和なことのためにアルキン及びイソニトリルの置換基の選択に非常に広い
許容範囲がある。 図２は(20S)-11-フルオロ-7-トリメチルシリルカンプトテシン12の合成に関す
る一般合成スキームの実施態様を示す。この合成スキームの問題は、アリールイ
ソニトリルの両方のオルト位が環化に利用できる（即ち、R4が式１の最終化合物
中でＨである）場合に遊離基カスケードの部位選択性を調節することである。こ
の問題の一つの解決策はアリールイソニトリルへのトリメチルシリル基の導入（
例えば、3-フルオロ-2-トリメチルシリルフェニルイソニトリル９）に頼る。ト リメチルシリル置換基は環化に対しイソニトリルのオルト位の一つをブロックし
、ヒドロデシリレーションによりカスケード反応後に除去し得る。この例におい
て、選択性はトリメチルシリル基の一つのみが最後の工程で除去されるという意
味で更に進行する。In general, various reagents may be used in the free radical cascade, including but not limited to hexamethyltin, hexamethyldisilane, or tetrakis (trimethylsilyl) silane. The source of energy for this reaction may be a solar or ultraviolet lamp. Preferably, the temperature is set between about 25C and 150C. More preferably, the temperature is set at about 70 ° C. There is no restriction on the choice of solvent used, other than being generally inert to the free radical cascade. Preferred solvents include benzene, toluene, acetonitrile, THF and tert-butanol. Also, because of the mild reaction conditions, there is a very wide latitude in the choice of alkyne and isonitrile substituents. FIG. 2 shows an embodiment of the general synthetic scheme for the synthesis of (20S) -11-fluoro-7-trimethylsilylcamptothecin 12. The problem with this synthetic scheme is that it modulates the regioselectivity of the free radical cascade when both ortho positions of the arylisonitrile are available for cyclization (ie, R 4 is H in the final compound of Formula 1). It is. One solution to this problem is to introduce a trimethylsilyl group into the arylisonitrile (
For example, rely on 3-fluoro-2-trimethylsilylphenyl isonitrile 9). The trimethylsilyl substituent blocks one of the ortho positions of isonitrile for cyclization and can be removed after the cascade reaction by hydrodecylation. In this example, the selectivity proceeds further in the sense that only one of the trimethylsilyl groups is removed in the last step.
【００２３】 幾つかの新規カンプトテシン誘導体の調製に関する一般合成スキームのその他
の実施態様が図３〜６、及び実施例に示される。 本発明はカンプトテシンファミリーにおける既知の構造−活性関係に良く適し
た短く、かつ有効な合成スキームを提供する。実際に、カンプトテシン骨格の生
物活性は７位及び／または9-11位以外の置換基に対し不耐性であり、又は非常に
わずかな寛容性を有する。合成後に、これらの置換基が夫々アルキニル誘導体３
及びアリールイソニトリル５により導入される。 抗腫瘍活性 式１の幾つかの化合物の抗腫瘍活性が表１に示され、幾つかの公知のカンプト
テシン類似体の抗腫瘍活性と比較される。表１に示された本発明の種々の例示化
合物の合成がこの節の後の実施例の節に更に詳しく説明される。 表１（２０Ｓ）−７−シリル−カンプトテシン誘導体の生物活性Other embodiments of the general synthetic scheme for the preparation of some novel camptothecin derivatives are shown in FIGS. The present invention provides short and efficient synthetic schemes that are well suited for known structure-activity relationships in the camptothecin family. In fact, the biological activity of the camptothecin skeleton is intolerant to substituents other than positions 7 and / or 9-11 or has very little tolerance. After synthesis, each of these substituents is replaced by an alkynyl derivative 3
And aryl isonitrile 5. Antitumor activity The antitumor activity of some compounds of Formula 1 is shown in Table 1 and is compared to the antitumor activity of some known camptothecin analogs. The synthesis of various exemplary compounds of the invention shown in Table 1 is described in further detail in the Examples section that follows this section. Table 1 Biological activity of (20S) -7-silyl-camptothecin derivatives
【００２４】[0024]
【表１】 [Table 1]
【００２５】 a)OPP＝イリノテカンのピロリジニルピロリジンカルバメート；TMS＝トリメチル
シリル；TBDMS＝t-ブチルジメチルシリル；TBDPS＝t-ブチルジフェニルシリル；
TES＝トリエチルシリル；TIPS＝トリイソプロピルシリル；DMNPS＝ジメチルイノ
ルピニルシリル；DMCPS＝ジメチル-3-シアノプロピルシリル；DMHPS＝ジメチル-
3-ハロプロピルシリル；b)BD2F1マウス試験でS-180中でCPTよりも更に活性 c)
BD2F1マウスでルイス肺癌腫中でCPTよりも更に活性。 表１に示されるように、本発明の化合物はカンプトテシン(CPT)及びイリノテ カン(IRT)と較べて良好乃至優れた抗腫瘍活性を示す。A) OPP = pyrrolidinylpyrrolidine carbamate of irinotecan; TMS = trimethylsilyl; TBDMS = t-butyldimethylsilyl; TBDPS = t-butyldiphenylsilyl;
TES = triethylsilyl; TIPS = triisopropylsilyl; DMNPS = dimethylinorpinylsilyl; DMCPS = dimethyl-3-cyanopropylsilyl; DMHPS = dimethyl-
3-halopropyl silyl; b) BD 2 F 1 further activity c than CPT in S-180 in mouse studies)
BD 2 F 1 mice with more active than CPT in Lewis lung carcinoma in. As shown in Table 1, the compounds of the present invention show good to excellent antitumor activity compared to camptothecin (CPT) and irinotecan (IRT).
【００２６】細胞毒性アッセイ カンプトテシン誘導体をin vitroでHL-60（ヒト前骨髄細胞白血病）細胞、833
K（ヒト奇形癌）細胞及びDC-3F（ハムスター肺）細胞の増殖に関するそれらの細
胞毒性効果について評価した。細胞を5 x 10-4細胞/mlの初期密度で培養した。 それらを５％CO2保湿雰囲気中で37℃でペニシリン(100u/ml)／ストレプトマイシ
ン(100μg/ml) (GIBCO-BRL)及び10％熱不活化ウシ胎児血清を含むRPMI-1640培地
(GIBCO-BRL グランドアイランド、ニューヨーク)中で管理した。そのアッセイを
96ウェルミクロプレート中で２回反復で行った。72時間のインキュベーション後
のHL-60細胞に対する化合物の細胞毒性をXTT微量培養テトラゾリウムアッセイに
より測定した。Scudiero, D.A.ら, Cancer Res., 48, 4827 (1988)（その開示が
参考として本明細書に含まれる）を参照のこと。2',3'-ビス-（メトキシ-4-ニト
ロ-5-スルフェニル）-5-〔（フェニルアミノ）カルボニル〕-2H-テトラゾリウム
ヒドロキシド(XTT)を血清を含まない前もって温めた（37℃）媒体中で1mg/mlで 調製した。フェナジンメソスルフェート(PMS)及び新しいXTTを一緒に混合して0.
075 mM PMS-XTT溶液を得た（5 mM PMS原液25μlを1 mg/ml XTT 5 ml当りに添加 した）。この混合物50μlを72時間のインキュベーションの終了時に細胞培養液 の夫々のウェルに添加した。37℃で４時間のインキュベーション後に、450nm及 び630nmにおける吸光度をミクロプレートリーダー（EL340、バイオ−テク・イン
ストルメンツ社、ウィノースキイ、バーモント）で測定した。 833K奇形癌充実性腫瘍細胞及びDC-3Fハムスター肺細胞に対するカンプトテシ ン化合物の細胞毒性を細胞タンパク質濃度を測定するためのSkehanらにより記載
された方法により96ウェルミクロプレート中で測定した。Skehanら,“New Color
ometric Cytotoxicity Assay for Anticancer Drug Screening", J. Nat'l Canc
er Inst., 82, 1107 (1990)（その開示が参考として本明細書に含まれる）を参 照のこと。培養液をトリクロロ酢酸で定着し、次いで１％酢酸に溶解した0.4％ スルフォーローダミンＢで30分間にわたって染色した。未結合色素を酢酸洗浄液
により除去し、タンパク質結合色素を96ウェルミクロプレートリーダー中で570n
mにおける吸光度の測定のために未緩衝トリス塩基〔トリス（ヒドロキシ−メチ ル）アミノメタン〕で抽出した。５〜６種の濃度の試験薬物を使用して、実験を
２回反復で行った。データをコンピュータ・ソフトウェアにより分析した。Chou
, J.及びChou, T.C., Dose-Effect Analysis With Microcomputers: Quantitati
on of ED50, LD50, Synergism, Antagonism, Low-Dose Risk, Receptor-Ligand
Binding and Enzyme Kinetics,第２編, Biosoft, Cambridge (1987);及びChou,
T.C.,“The Median-Effect Principle and the Combination Index for Quantit
ation of Synergism and Antagonism", Synergism and Antagonism in Chemothe
rapy, Academic Press, San Diego, 61-102 (1991)（これらの開示が参考として
本明細書に含まれる）を参照のこと。 Cytotoxicity assay Camptothecin derivatives were tested in vitro with HL-60 (human promyelocytic leukemia) cells, 833.
Their cytotoxic effects on proliferation of K (human teratocarcinoma) cells and DC-3F (hamster lung) cells were evaluated. Cells were cultured at an initial density of 5 × 10 −4 cells / ml. RPMI-1640 medium containing penicillin (100 u / ml) / streptomycin (100 μg / ml) (GIBCO-BRL) and 10% heat-inactivated fetal bovine serum at 37 ° C. in a 5% CO 2 humidified atmosphere.
(GIBCO-BRL Grand Island, New York). The assay
Performed in duplicate in 96-well microplates. The cytotoxicity of the compound on HL-60 cells after 72 hours of incubation was determined by XTT microculture tetrazolium assay. See Scudiero, DA et al., Cancer Res., 48, 4827 (1988), the disclosure of which is incorporated herein by reference. 2 ', 3'-bis- (methoxy-4-nitro-5-sulfenyl) -5-[(phenylamino) carbonyl] -2H-tetrazolium hydroxide (XTT) was pre-warmed without serum (37 ° C). ) Prepared at 1 mg / ml in medium. Mix phenazine meso sulfate (PMS) and fresh XTT together.
A 075 mM PMS-XTT solution was obtained (25 μl of a 5 mM PMS stock solution was added per 5 ml of 1 mg / ml XTT). 50 μl of this mixture was added to each well of cell culture at the end of the 72 hour incubation. After incubation at 37 ° C for 4 hours, the absorbance at 450 nm and 630 nm was measured with a microplate reader (EL340, Bio-Tech Instruments, Winnose Key, VT). The cytotoxicity of the camptothecin compound on 833K teratocarcinoma solid tumor cells and DC-3F hamster lung cells was measured in 96-well microplates by the method described by Skehan et al. For measuring cellular protein concentrations. Skehan et al., “New Color
metric Cytotoxicity Assay for Anticancer Drug Screening ", J. Nat'l Canc
er Inst., 82, 1107 (1990), the disclosure of which is incorporated herein by reference. Cultures were fixed with trichloroacetic acid and then stained with 0.4% sulforhodamine B in 1% acetic acid for 30 minutes. Unbound dye is removed with an acetic acid wash and protein bound dye is removed in a 96-well microplate reader for 570 n.
Extraction with unbuffered Tris base [tris (hydroxy-methyl) aminomethane] for measurement of absorbance at m. The experiment was performed in duplicate using 5-6 concentrations of test drug. Data was analyzed by computer software. Chou
, J. and Chou, TC, Dose-Effect Analysis With Microcomputers: Quantitati
on of ED 50 , LD 50 , Synergism, Antagonism, Low-Dose Risk, Receptor-Ligand
Binding and Enzyme Kinetics, Vol. 2, Biosoft, Cambridge (1987); and Chou,
TC, “The Median-Effect Principle and the Combination Index for Quantit
ation of Synergism and Antagonism ", Synergism and Antagonism in Chemothe
See rapy, Academic Press, San Diego, 61-102 (1991), the disclosures of which are incorporated herein by reference.
【００２７】トポＩ媒介DNA開裂アッセイ DNA開裂アッセイについて、その反応混合物は既に記載されたように20μlの最
終容積で精製DNAトポイソメラーゼＩの存在下でTris-HCl緩衝液10 mM、pH7.5; P
BR322超らせん二本鎖環状DNA（ベーリンガー・マンハイム・バイオケミカルズか
らの4363塩基対）0.125μg/ml、１、10及び100μMの濃度の薬物（カンプトテシ ン又はその誘導体）を含んでいた。Hsiang, Y.H.ら,“Camptothecin Induces Pr
otein-linked DNA Breaks Via Mammalian DNA Topoisomerase I", J. Biol. Che
m., 260, 14873 (1985)（その開示が参考として本明細書に含まれる）を参照の こと。インキュベーションを37℃で60分間にわたって行った。ローディング緩衝
剤色素（２％ドデシル硫酸ナトリウム、0.05％ブロモフェノール・ブルー及び６
％グリセロール）を添加することにより反応を停止した。電気泳動をTBE緩衝液 （Tris-塩基-ホウ酸-EDTA）中で１％アガロースゲル＋臭化エチジウム（１μg/m
l）で行い、25Vで18時間にわたって実験した。ポラロイドフィルム型55/Nを使用
して写真を紫外線の下で撮影し、製造業者により示されたようにして現像した。 Topo I-Mediated DNA Cleavage Assay For the DNA Cleavage Assay, the reaction mixture was prepared as described previously in a final volume of 20 μl in the presence of purified DNA topoisomerase I in 10 mM Tris-HCl buffer, pH 7.5;
BR 322 supercoiled double-stranded circular DNA (4363 base pairs from Boehringer Mannheim Biochemicals) 0.125 [mu] g / ml, contained 1, 10 and 100μM concentrations of the drug (Kanputoteshi down or derivatives thereof). Hsiang, YH et al., “Camptothecin Induces Pr
otein-linked DNA Breaks Via Mammalian DNA Topoisomerase I ", J. Biol. Che
m., 260, 14873 (1985), the disclosure of which is incorporated herein by reference. Incubation was performed at 37 ° C. for 60 minutes. Loading buffer dye (2% sodium dodecyl sulfate, 0.05% bromophenol blue and 6%
% Glycerol) was stopped. Electrophoresis was performed in 1% agarose gel + ethidium bromide (1 µg / m2) in TBE buffer (Tris-base-boric acid-EDTA).
l) and experimented at 25V for 18 hours. Pictures were taken under UV light using Polaroid film type 55 / N and developed as indicated by the manufacturer.
【００２８】超らせんDNAのトポＩ媒介弛緩の抑制 DNAのDNAトポイソメラーゼＩ媒介弛緩に関する抑制効果を研究するために、Li
u及びMillerにより記載された方法を使用した。Liu, H.F.ら,“Cleavage of DNA
by Mammalian DNA Topoisomerase II", J. Biol. Chem., 258, 15365 (1980)（
その開示が参考として本明細書に含まれる）を参照のこと。このアッセイのため
に、50 mM Tris-HCl, pH 7.5、120 mM KCl、10 mM MgCl2、0.5 mM DTT、0.5 mM
EDTA、30μg/mlのBSA、20μg/mlのPBR322 DNA及び種々の量の酵素を含む反応混 合物（20μl）中のPBR322 DNA 0.18μg、トポＩ (GIBCO-BRL) 0.5 U、種々の濃 度（1-100μM）のカンプトテシン又は類似体を37℃で30分間にわたってインキュ
ベートし、５％SBS及び150μg/mlのプロテイナーゼＫで停止した。サンプルをTA
E運転緩衝液中１％アガロースに装填し、39Vで一夜電気泳動し、EtBrで染色し、
紫外線の下で写真撮影した。 Inhibition of topoI-mediated relaxation of supercoiled DNA To study the inhibitory effect of DNA on DNA topoisomerase I-mediated relaxation, Li
The method described by u and Miller was used. Liu, HF et al., “Cleavage of DNA
by Mammalian DNA Topoisomerase II ", J. Biol. Chem., 258, 15365 (1980) (
The disclosure of which is incorporated herein by reference). For this assay, 50 mM Tris-HCl, pH 7.5,120 mM KCl, 10 mM MgCl 2, 0.5 mM DTT, 0.5 mM
EDTA, a 30μg / ml BSA, 20μg / ml of PBR 322 DNA and the reaction mixed-containing varying amounts of enzyme (20 [mu] l) in the PBR 322 DNA 0.18, topo I (GIBCO-BRL) 0.5 U , various Concentrations (1-100 μM) of camptothecin or analog were incubated at 37 ° C. for 30 minutes and stopped with 5% SBS and 150 μg / ml proteinase K. TA sample
E Load 1% agarose in running buffer, electrophorese at 39V overnight, stain with EtBr,
Photographed under UV light.
【００２９】in vivoの抗腫瘍活性 カンプトテシン誘導体の抗腫瘍活性を肉腫-180又はルイス肺マウス充実性腫瘍
を有するB6D2F1マウスで試験した。S-180について、3 x 106細胞を３日目に皮下
に接種した。抗腫瘍治療が５日間にわたって毎日２回の腹腔内で１日目に開始し
た。７日目及び14日目に腫瘍体積を測定した。平均腫瘍体積を治療したもの対未
治療対照の比(T/C)として記載した。７日目及び14日目に関する対照（DMSOビヒ クルのみで措置した）腫瘍体積は夫々0.11cm3及び0.61cm3であった。T/Cカンプ トテシンを“+++”で表示する。2mg/kgの投与量で14日目のカンプトテシンT/Cと
較べて10％の増分又は減分を夫々一つの“+”単位の増加又は減少で表示する。 ルイス肺癌について、腫瘍細胞（1 x 106）を０日目に皮下接種し、治療が５ 日間にわたって毎日２回の腹腔内で１日目に開始した。効果の等級付けは上記の
とおりであった。 表１に示されたように、in vitroの抗腫瘍細胞毒性について試験したカンプト
テシン誘導体の多くが１種〜３種の細胞系でカンプトテシンよりも高い効力を示
した。また、高い抗腫瘍細胞毒性を示すこれらの化合物の殆どがPBR322DNAのDNA
トポイソメラーゼＩ媒介開裂を増進し、又はPBR322DNAのDNAトポイソメラーゼＩ
媒介弛緩を抑制するのに高い効力を示した。これらの結果はDNAトポイソメラー ゼＩの機能を抑制するそれらの能力とカンプトテシン化合物の抗腫瘍細胞毒性の
間の優れた相関関係を示唆する。 腫瘍を有するマウスにおけるin vivo化学療法効果について、例えば、7-トリ メチルシリルカンプトテシンは腫瘍体積減少に関して投与量依存様式で幾つかの
均等投与量でB6D2F1マウスで肉腫180に対しカンプトテシンよりも良好な活性を 示した。同様に、ルイス肺癌腫について、7-トリメチルシリル-11-フルオロカン
プトテシンはカンプトテシンよりも４倍少ない投与量で腫瘍体積減少に関してカ
ンプトテシンと同様の抗腫瘍効果を示した。こうして、7-トリメチルシリル-11-
フルオロカンプトテシンはin vivoのその抗腫瘍効果でカンプトテシンよりも効 力がある。 こうして、本発明者らはカンプトテシン構造の７位におけるシリル基（例えば
、トリメチルシリル基）の導入がカンプトテシンよりも良好な抗腫瘍活性を有す
る化合物を典型的にもたらすことを発見した（例えば、(20S)-CPTと較べて実施 例１の化合物を参照のこと）。また、シリル基はイリノテカン系列に有益である
（例えば、イリノテカンと較べて実施例６の化合物を参照のこと）。[0029] was tested the antitumor activity of anti-tumor activity of camptothecin derivatives in vivo in B 6 D 2 F 1 mice with sarcoma -180 or Lewis lung murine solid tumor. For S-180, 3 × 10 6 cells were inoculated subcutaneously on day 3. Antitumor treatment started on day 1 intraperitoneally twice daily for 5 days. Tumor volumes were measured on days 7 and 14. Mean tumor volume was reported as the ratio of treated to untreated control (T / C). Control for 7 and 14 days (and measures only with DMSO bi arsenide cycle) Tumor volume was respectively 0.11 cm 3 and 0.61 cm 3. Displays T / C comptothecin as “+++”. At a dose of 2 mg / kg, a 10% increase or decrease compared to day 14 camptothecin T / C is indicated by a single “+” unit increase or decrease, respectively. For Lewis lung carcinoma, tumor cells (1 × 10 6 ) were inoculated subcutaneously on day 0 and treatment started on day 1 intraperitoneally twice daily for 5 days. The grading of the effects was as described above. As shown in Table 1, many of the camptothecin derivatives tested for in vitro antitumor cytotoxicity showed higher potency than camptothecin in one to three cell lines. Also, higher exhibits antitumor cytotoxicity Most of these compounds of PBR 322 DNA DNA
Enhances topoisomerase I-mediated cleavage, or enhances DNA topoisomerase I of PBR322 DNA
It was highly effective in inhibiting mediated relaxation. These results suggest an excellent correlation between their ability to suppress the function of DNA topoisomerase I and the antitumor cytotoxicity of camptothecin compounds. For in vivo chemotherapeutic effects in tumor-bearing mice, for example, camptothecin to 7-trimethyl silyl camptothecin B 6 D 2 F 1 Sarcoma 180 in mice in several equivalent doses in a dose-dependent manner with respect to tumor volume reduction It showed better activity. Similarly, for Lewis lung carcinoma, 7-trimethylsilyl-11-fluorocamptothecin showed a similar anti-tumor effect as camptothecin in reducing tumor volume at 4-fold lower dose than camptothecin. Thus, 7-trimethylsilyl-11-
Fluorocamptothecin is more potent than camptothecin in its antitumor effects in vivo. Thus, the present inventors have discovered that the introduction of a silyl group at position 7 of the camptothecin structure (eg, a trimethylsilyl group) typically results in compounds having better antitumor activity than camptothecin (eg, (20S) (See compound of Example 1 compared to -CPT). Silyl groups are also beneficial to the irinotecan series (see, for example, the compound of Example 6 compared to irinotecan).
【００３０】 抗腫瘍活性は、ヒドロキシ基が実施例１の化合物の10位に導入されて実施例５
の化合物を生成する時に実質的に変化されないままである。実施例６の化合物は
イリノテカンの活性代謝産物であるSN-38の類縁体である。最高の活性の幾つか がトリメチルシリル基を11位でフルオロ原子（例えば、実施例７の化合物を参照
のこと）、又は10位もしくは11位で一級アミン基（夫々、実施例８及び９を参照
のこと）と一緒に導入した時に本研究で観察された。また、12位のフルオロ原子
の導入がカンプトテシンよりも約２倍効力の小さい類似体をもたらす（(20S)-CP
Tと較べて実施例11を参照のこと）。この結果は、文献に既に報告された12-置換
カンプトテシンの不充分な活性を考えると驚くべきことである。 こうして、哺乳類（ヒト又は動物）が医薬有効量の式(1)の化合物又はその医 薬上許される塩の哺乳類への投与を含む方法により治療し得る。哺乳類の症状が
それにより改善し得る。 本発明の化合物は、例えば、非経口（例えば、静脈内、皮内、筋肉内又は皮下
）、経口（例えば、錠剤、ロゼンジ剤、カプセル、懸濁液又は液体溶液の形態で
）、座薬の形態で直腸又は膣、又は局所（例えば、ペースト、クリーム、ゲル又
はローションとして）を含む種々の投薬形態で投与し得る。 投与される最適投与量は当業者により決められ、使用される式(1)の特別な化 合物、製剤の濃度、投与の様式、投与の時間及び頻度、並びに患者の症状の進行
により変化するであろう。特別な患者に応じた付加的な因子が投薬量を調節する
必要を生じるであろう。このような因子として、患者の年齢、体重、性及び食事
が挙げられる。投与量は一度に投与されてもよく、又は時間の種々の間隔で投与
される幾つかの少量の投薬量に分けられてもよい。The antitumor activity was measured in Example 5 by introducing a hydroxy group at the 10-position of the compound of Example 1.
Remains substantially unchanged when producing the compound of formula (I). The compound of Example 6 is an analog of SN-38, an active metabolite of irinotecan. Some of the highest activities include trimethylsilyl groups at the 11 position with a fluoro atom (see, for example, the compound of Example 7) or at the 10 or 11 position with a primary amine group (see Examples 8 and 9, respectively). Was observed in this study when introduced together. Also, introduction of a fluoro atom at position 12 results in an analog that is approximately twice as potent as camptothecin ((20S) -CP
See Example 11 compared to T). This result is surprising given the insufficient activity of 12-substituted camptothecins already reported in the literature. Thus, a mammal (human or animal) can be treated by a method comprising administering to the mammal a pharmaceutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof. The condition of the mammal can thereby be improved. The compounds of the invention may be for example parenterally (eg, intravenous, intradermal, intramuscular or subcutaneous), oral (eg, in the form of tablets, lozenges, capsules, suspensions or liquid solutions), suppository forms And may be administered in a variety of dosage forms, including rectally or vaginally, or topically (eg, as a paste, cream, gel or lotion). The optimal dose to be administered is determined by one skilled in the art and will vary with the particular compound of formula (1) used, the concentration of the formulation, the mode of administration, the time and frequency of administration, and the progress of the patient's condition. Will. Additional factors depending on the particular patient will require the dosage to be adjusted. Such factors include the age, weight, sex and diet of the patient. The dose may be administered at once, or may be divided into a number of smaller doses to be administered at various intervals of time.
【００３１】 （実施例） 以下の実施例は本発明の説明のために示され、本発明を限定することを目的と
するのではない。 実施例1 (20S)-7-トリメチルシリルカンプトテシンの製造EXAMPLES The following examples are provided for the purpose of illustrating the present invention and are not intended to limit the present invention. Example 1 Production of (20S) -7-trimethylsilylcamptothecin
【００３２】 [0032]
【００３３】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オキソ-7-(3-トリメチルシリル-2-
プロピニル)-1H-ピラノ[3,4-c]-8-ピリドン DME(2.5 mL)及びDMF(0.60 mL)中の(S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オ
キソ-1H-ピラノ[3,4-c]-8-ピリドン [ヨードピリドン (2), 250 mg, 0.746 mmol
]溶液に、0℃、アルゴン下、鉱油中の60% NaH(31.3 mg, 0.783 mmol)を添加した
。LiBr (150 mg, 1.75 mmol)を10分後に添加した。室温で15分後、3-トリメチル
シリル-2-プロピニルブロミド(430 mg, 2.24 mmol)を注入し、反応混合物を暗中
、65℃で20時間加熱した。最終の溶液を塩水(20 mL)へ注ぎ、AcOEt(6 x 15 mL) で抽出し、乾燥(Na2SO4)した。溶媒の除去後に得られた残渣をフラッシュクロマ
トグラフィー(CHCl3/AcOEt 95:5)に付し、283mg(85%)のフォームを得た:[]20 D +
36.7 (c 1, CHCl3); IR (ニート（neat）, cm 1) 3384, 2940, 2166, 1730, 163
4, 1518, 1406, 1130, 841, 752; 1H NMR (300 MHz, CDCl3) 0.14 (s, 9 H),
0.95 (t, J = 7.4 Hz, 3 H), 1.77 (m, 2 H), 3.66 (s, 1 H), 5.00 (d, J = 17
.2 Hz, 1 H), 5.10 (d, J = 16.4 Hz, 1 H), 5.15 (d, J = 17.2 Hz, 1 H), 5.4
9 (d, J = 16.4 Hz, 1 H), 7.16 (s, 1 H); 13C NMR (75 MHz, CDCl3) 0.40,
7.7, 31.5, 44.5, 66.3, 71.8, 90.9, 97.9, 116.5, 118.1, 148.6, 157.9, 173
.3; C16H20INO4Si (M+) について計算したHRMS (EI) m/z 445.0206,実測値445.
0203; LRMS (EI) m/z 445 (M+), 430, 416, 386.(1) (S) -4-ethyl-4-hydroxy-6-iodo-3-oxo-7- (3-trimethylsilyl-2-
(Propinyl) -1H-pyrano [3,4-c] -8-pyridone (S) -4-ethyl-4-hydroxy-6-iodo-3-o in DME (2.5 mL) and DMF (0.60 mL)
Kiso-1H-pyrano [3,4-c] -8-pyridone [iodopyridone (2), 250 mg, 0.746 mmol
] Solution was added 60% NaH in mineral oil (31.3 mg, 0.783 mmol) at 0 ° C under argon
. LiBr (150 mg, 1.75 mmol) was added after 10 minutes. After 15 minutes at room temperature, 3-trimethyl
Silyl-2-propynyl bromide (430 mg, 2.24 mmol) was injected and the reaction mixture was left in the dark.
And heated at 65 ° C. for 20 hours. The final solution was poured into brine (20 mL), extracted with AcOEt (6 x 15 mL), dried (NaTwoSOFour)did. The residue obtained after solvent removal is flash chromatographed.
Tography (CHClThree/ AcOEt 95: 5) to give 283 mg (85%) of the foam: []20 D +
36.7 (c 1, CHClThree); IR (neat, cm 1) 3384, 2940, 2166, 1730, 163
4, 1518, 1406, 1130, 841, 752;1H NMR (300 MHz, CDClThree) 0.14 (s, 9 H),
0.95 (t, J = 7.4 Hz, 3 H), 1.77 (m, 2 H), 3.66 (s, 1 H), 5.00 (d, J = 17
.2 Hz, 1 H), 5.10 (d, J = 16.4 Hz, 1 H), 5.15 (d, J = 17.2 Hz, 1 H), 5.4
9 (d, J = 16.4 Hz, 1 H), 7.16 (s, 1 H);13C NMR (75 MHz, CDClThree) 0.40,
7.7, 31.5, 44.5, 66.3, 71.8, 90.9, 97.9, 116.5, 118.1, 148.6, 157.9, 173
.3; C16HTwo0INOFourSi (M+HRMS (EI) m / z 445.0206 calculated for), found 445.
0203; LRMS (EI) m / z 445 (M+), 430, 416, 386.
【００３４】 (2) (20S)-7-トリメチルシリルカンプトテシン (1)で製造した化合物(36.6 mg, 0.082 mmol)、フェニル イソニトリル(0.25 m
mol)及びヘキサメチルジチン(42 mg, 0.123 mmol)のベンゼン(1.3 mL)溶液に、 アルゴン下、70℃で、275W GE サンランプ（sunlamp）を10時間照射した。最終 の反応混合物を濃縮し、フラッシュクロマトグラフィー(CHCl3/MeOH 96:4)に付 し18.8mg(54%)のわずかに黄色の固体を得た:[]20 D +39.0 (c 0.2, CHCl3/MeOH 4
:1); 1H NMR (300 MHz, CDCl3/CD3OD 3:1) 0.50 (s, 9 H), 0.83 (t, J = 7.4
Hz, 3 H), 1.74 (m, 2 H), 3.72 (br s, 1 H), 5.12 (d, J = 16.4 Hz, 1 H),
5.16 (br s, 2 H), 5.47 (d, J = 16.4 Hz, 1 H), 7.49 (t, J = 8.1 Hz, 1 H),
7.54 (s, 1 H), 7.62 (t, J = 8.1 Hz, 1 H), 8.02 (d, J = 8.1 Hz, 1 H), 8.
07 (d, J = 8.1 Hz, 1 H); 13C NMR (75 MHz, CDCl3/CD3OD 3:1) 0.9, 7.2, 2
9.3, 31.0, 51.7, 65.5, 98.3, 118.4, 127.3, 128.0, 129.7, 130.0, 131.8, 1
34.3, 144.7, 145.6, 147.3, 151.1, 173.5; C23H24N2O4Si (M+) について計算
したHRMS (EI) m/z 420.1505,実測値420.1501; LRMS (EI) m/z 420 (M+), 391,
376, 361, 347, 320, 291. 実施例2 (20S)-7-tert-ブチルジメチルシリルカンプトテシンの製造(2) Compound (36.6 mg, 0.082 mmol) prepared using (20S) -7-trimethylsilylcamptothecin (1), phenyl isonitrile (0.25 m
mol) and hexamethylditin (42 mg, 0.123 mmol) in benzene (1.3 mL) were irradiated with a 275 W GE sunlamp at 70 ° C. under argon for 10 hours. The final reaction mixture was concentrated and subjected to flash chromatography (CHCl 3 / MeOH 96: 4) to give 18.8 mg (54%) of a slightly yellow solid: [] 20 D +39.0 (c 0.2, CHCl 3 3 / MeOH 4
: 1); 1 H NMR (300 MHz, CDCl 3 / CD 3 OD 3: 1) 0.50 (s, 9 H), 0.83 (t, J = 7.4
Hz, 3 H), 1.74 (m, 2 H), 3.72 (br s, 1 H), 5.12 (d, J = 16.4 Hz, 1 H),
5.16 (br s, 2 H), 5.47 (d, J = 16.4 Hz, 1 H), 7.49 (t, J = 8.1 Hz, 1 H),
7.54 (s, 1 H), 7.62 (t, J = 8.1 Hz, 1 H), 8.02 (d, J = 8.1 Hz, 1 H), 8.
07 (d, J = 8.1 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 / CD 3 OD 3: 1) 0.9, 7.2, 2
9.3, 31.0, 51.7, 65.5, 98.3, 118.4, 127.3, 128.0, 129.7, 130.0, 131.8, 1
34.3, 144.7, 145.6, 147.3, 151.1, 173.5; C 23 H 24 N 2 O 4 Si (M +) for calculated HRMS (EI) m / z 420.1505 , Found 420.1501; LRMS (EI) m / z 420 ( M + ), 391,
376, 361, 347, 320, 291. Example 2 Production of (20S) -7-tert-butyldimethylsilylcamptothecin
【００３５】 [0035]
【００３６】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オキソ-7-(3-tert-ブチルジメチル
シリル-2-プロピニル)-1H-ピラノ[3,4-c]-8-ピリドン 実施例1-(1)に記載の手順に従い, ヨードピリドン (2) (200 mg, 0.60 mmol)
及び3-tert-ブチルジメチルシリル-2-プロピニルブロミド (280 mg, 1.20 mmol)
を提供し、フラッシュクロマトグラフィー (CH2Cl2/AcOEt 9:1)後に、173mg(59%
)の白色のフォームを得た:[]20 D +58 (c 0.2, CHCl3); IR (CHCl3, cm-1) 3548
, 2950, 2927, 2859, 1745, 1648, 1526; 1H NMR (300 MHz, CDCl3) 0.08 (s,
6 H), 0.92 (m, 12 H), 1.79 (m, 2 H), 3.77 (br s, 1 H), 5.00-5.25 (m, 3
H), 5.50 (d, J = 16.4 Hz, 1 H) 7.19 (s, 1 H); 13C NMR (75 MHz, CDCl3)
4.9, 7.63, 16.6, 26.0, 31.6, 44.5, 66.3, 71.8, 89.4, 98.6, 100.0, 116.5,
118.1, 148.6, 158.0, 173.2; C19H26INO4Si (M+)について計算したHRMS (EI)
m/z 487.0679,実測値487.0676; LRMS (EI) m/z 487 (M+), 430, 386, 96, 81,
57.(1) (S) -4-ethyl-4-hydroxy-6-iodo-3-oxo-7- (3-tert-butyldimethylsilyl-2-propynyl) -1H-pyrano [3,4- c] -8-Pyridone According to the procedure described in Example 1- (1), iodopyridone (2) (200 mg, 0.60 mmol)
And 3-tert-butyldimethylsilyl-2-propynylbromide (280 mg, 1.20 mmol)
173 mg (59%) after flash chromatography (CH 2 Cl 2 / AcOEt 9: 1).
) Was obtained: [] 20 D +58 (c 0.2, CHCl 3 ); IR (CHCl 3 , cm −1 ) 3548
, 2950, 2927, 2859, 1745, 1648, 1526; 1 H NMR (300 MHz, CDCl 3 ) 0.08 (s,
6 H), 0.92 (m, 12 H), 1.79 (m, 2 H), 3.77 (br s, 1 H), 5.00-5.25 (m, 3
H), 5.50 (d, J = 16.4 Hz, 1 H) 7.19 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 )
4.9, 7.63, 16.6, 26.0, 31.6, 44.5, 66.3, 71.8, 89.4, 98.6, 100.0, 116.5,
118.1, 148.6, 158.0, 173.2; C 19 H 26 INO 4 Si (M +) HRMS calculated for (EI)
m / z 487.0679, found 487.0676; LRMS (EI) m / z 487 (M + ), 430, 386, 96, 81,
57.
【００３７】 (2) (20S)-7-tert-ブチルジメチルシリルカンプトテシン 実施例1-(2)に記載した手順に従い、 (1)で製造した化合物(48.7 mg, 0.10 mm
ol)を提供し、フラッシュクロマトグラフィー (CH2Cl2/MeOH 96:4; CH2Cl2/アセ
トン 9:1)後に、24.8 mg(54%)のオフイエロー色の固体を得た: []20 D +35.5 (c
0.2, CHCl3); IR (CHCl3, cm-1) 3028, 2980, 2960, 2932, 2859, 1741, 1658
, 1600, 1555, 1257, 1198, 1158, 1045; 1H NMR (300 MHz, CDCl3) 0.69 (s,
6 H), 0.98 (s, 9 H), 1.03 (t, J = 7.3 Hz, 3 H), 1.86 (m, 2 H), 3.86 (s,
1 H), 5.29 (d, J = 16.3 Hz, 1 H), 5.31 (s, 2 H), 5.73 (d, J = 16.3 Hz,
1 H), 7.60 (t, J = 6.3 Hz, 1 H), 7.60 (t, J = 7.0 Hz, 1 H), 7.66 (s, 1 H
), 7.74 (t, J = 7.3 Hz, 1 H) 8.20 (t, J = 8.1 Hz, 2 H); 13C NMR (75 MHz
, CDCl3) -0.56, 7.80, 19.2, 27.1, 31.6, 52.4, 66.3, 72.8, 97.7, 118.2,
127.0, 129.5, 129.6, 130.8, 132.7, 136.0, 143.0, 146.4, 148.0, 150.1, 15
0.6, 157.4, 173.9; C26H30N2O4Si (M+) について計算したHRMS (EI) m/z 462.
1974,実測値462.1975; LRMS (EI) m/z 462 (M+), 450, 361, 331, 304, 245, 2
23, 57. 実施例3 (20S)-7-tert-ブチルジフェニルシリルカンプトテシンの製造(2) (20S) -7-tert-butyldimethylsilylcamptothecin The compound prepared in (1) (48.7 mg, 0.10 mm) according to the procedure described in Example 1- (2)
Provides ol), flash chromatography (CH 2 Cl 2 / MeOH 96 : 4; CH 2 Cl 2 / acetone 9: 1) after to give an off-yellow solid 24.8 mg (54%): [ ] 20 D +35.5 (c
0.2, CHCl 3 ); IR (CHCl 3 , cm -1 ) 3028, 2980, 2960, 2932, 2859, 1741, 1658
, 1600, 1555, 1257, 1198, 1158, 1045; 1 H NMR (300 MHz, CDCl 3 ) 0.69 (s,
6H), 0.98 (s, 9 H), 1.03 (t, J = 7.3 Hz, 3 H), 1.86 (m, 2 H), 3.86 (s,
1 H), 5.29 (d, J = 16.3 Hz, 1 H), 5.31 (s, 2 H), 5.73 (d, J = 16.3 Hz,
1H), 7.60 (t, J = 6.3 Hz, 1 H), 7.60 (t, J = 7.0 Hz, 1 H), 7.66 (s, 1 H
), 7.74 (t, J = 7.3 Hz, 1 H) 8.20 (t, J = 8.1 Hz, 2 H); 13 C NMR (75 MHz
, CDCl 3 ) -0.56, 7.80, 19.2, 27.1, 31.6, 52.4, 66.3, 72.8, 97.7, 118.2,
127.0, 129.5, 129.6, 130.8, 132.7, 136.0, 143.0, 146.4, 148.0, 150.1, 15
0.6, 157.4, 173.9; C 26 H 30 N 2 O 4 Si (M +) HRMS calculated for (EI) m / z 462.
1974, found 462.1975; LRMS (EI) m / z 462 (M + ), 450, 361, 331, 304, 245, 2
23, 57. Example 3 Production of (20S) -7-tert-butyldiphenylsilylcamptothecin
【００３８】 [0038]
【００３９】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オキソ-7-(3-tert-ブチルジフェニ
ルシリル-2-プロピニル)-1H-ピラノ[3,4-c]-8-ピリドン 実施例1-(1)に記載の手順に従い、ヨードピリドン (2) (200 mg, 0.60 mmol)
及び3-tert-ブチルジフェニルシリル-2-プロピニルブロミド (428 mg, 1.20 mmo
l)を提供し、フラッシュクロマトグラフィー (CH2Cl2/AcOEt 9:1)後に、258 mg
(70%)の白色のフォームを得た: []20 D +45.1 (c 0.2, CHCl3); IR (CHCl3, cm -1 ) 3546, 2928, 2855, 1741, 1658, 1526; 1H NMR (300 MHz, CDCl3) 0.97 (
t, J = 7.3 Hz, 3 H), 1.08 (s, 9 H), 1.80 (m, J = 7.1 Hz, 2 H), 3.76 (br
s, 1 H), 5.13 (d, J = 16.4 Hz, 1 H), 5.29 (d, J = 2.5 Hz, 2 H), 5.52 (d,
J = 16.4 Hz, 1 H), 7.22 (s, 1 H), 7.32-7.40 (m, 6 H), 7.76-7.78 (m, 4 H
); 13C NMR (75 MHz, CDCl3) 7.6, 18.6, 27.0, 31.6, 44.6, 60.4, 66.3, 71
.8, 86.5, 99.9, 102.2, 116.6, 127.7, 129.6, 132.6, 135.6, 148.7, 157.8,
173.2; C25H21INO4Si (M-C4H9 +) について計算したHRMS (EI) m/z 554.0279,実
測値554.0285; LRMS (EI) m/z 554 (M-C4H9 +), 587, 510, 220, 143, 105.(1) (S) -4-ethyl-4-hydroxy-6-iodo-3-oxo-7- (3-tert-butyldiphenyl
Lucylyl-2-propynyl) -1H-pyrano [3,4-c] -8-pyridone According to the procedure described in Example 1- (1), iodopyridone (2) (200 mg, 0.60 mmol)
And 3-tert-butyldiphenylsilyl-2-propynyl bromide (428 mg, 1.20 mmo
l) and provide flash chromatography (CHTwoClTwo/ AcOEt 9: 1), 258 mg
(70%) obtained a white foam: []20 D +45.1 (c 0.2, CHClThree); IR (CHClThree, cm -1 ) 3546, 2928, 2855, 1741, 1658, 1526;1H NMR (300 MHz, CDClThree) 0.97 (
t, J = 7.3 Hz, 3 H), 1.08 (s, 9 H), 1.80 (m, J = 7.1 Hz, 2 H), 3.76 (br
s, 1 H), 5.13 (d, J = 16.4 Hz, 1 H), 5.29 (d, J = 2.5 Hz, 2 H), 5.52 (d,
J = 16.4 Hz, 1 H), 7.22 (s, 1 H), 7.32-7.40 (m, 6 H), 7.76-7.78 (m, 4 H
);13C NMR (75 MHz, CDClThree) 7.6, 18.6, 27.0, 31.6, 44.6, 60.4, 66.3, 71
.8, 86.5, 99.9, 102.2, 116.6, 127.7, 129.6, 132.6, 135.6, 148.7, 157.8,
173.2; Ctwenty fiveHtwenty oneINOFourSi (M-CFourH9 +HRMS (EI) m / z 554.0279, calculated for
Found 554.0285; LRMS (EI) m / z 554 (M-CFourH9 +), 587, 510, 220, 143, 105.
【００４０】 (2) (20S)-7-tert -ブチルジフェニルシリルカンプトテシン 実施例1-(2)に記載の手順に従い、(1)で製造した化合物(61.1 mg, 0.10 mmol)
を提供し、フラッシュクロマトグラフィー (CH2Cl2/MeOH 96:4; CH2Cl2/アセト ン 9:1)後に、26.5 mg (45%)の明るい黄色の固体を得た: []20 D +35.2 (c 0.2,
CHCl3); IR (CHCl3, cm-1) 3003, 2984, 2969, 2958, 2935, 1741, 1658, 159
9, 1555, 1428, 1226, 1216, 1158, 1102; 1H NMR (300 MHz, CDCl3) 1.00 (t
, J = 7.3 Hz, 3 H), 1.44 (s, 9 H), 1.84 (m, 2 H), 3.75 (s, 1 H), 4.21 (d
, J = 5.7 Hz, 2 H), 5.19 (d, J = 16.3 Hz, 1 H), 5.64 (d, J = 16.3 Hz, 1
H), 7.43 (m, 5 H), 7.51 (t, J = 7.3 Hz, 2 H), 7.62 (s, 1 H), 7.69 (m, 5
H), 8.10 (d, J = 8.5 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 1 H); 13C NMR (75 M
Hz, CDCl3) 7.9, 20.4, 30.2, 31.6, 52.2, 66.4, 72.8, 97.5, 118.2, 126.3,
128.6, 129.8, 130.3, 130.7, 131.9, 132.2, 134.6, 134.64, 136.4, 136.5,
138.1, 140.9, 146.2, 148.4, 149.9, 151.3, 157.1, 174.1; C36H34N2O4Si (M + ) について計算したHRMS (EI) m/z 586.2281,実測値586.2288; LRMS (EI) m/z
586 (M+), 542, 529, 485, 428, 407, 321, 181, 131, 69. 実施例4 (20S)-10-アセトキシ-7-トリメチルシリルカンプトテシンの製造 (図3参照)(2) (20S) -7-tert-butyldiphenylsilylcamptothecin The compound produced in (1) according to the procedure described in Example 1- (2) (61.1 mg, 0.10 mmol)
Provide flash chromatography (CHTwoClTwo/ MeOH 96: 4; CHTwoClTwoAfter 9: 1) / acetone, 26.5 mg (45%) of a light yellow solid were obtained: []20 D +35.2 (c 0.2,
CHClThree); IR (CHClThree, cm-1) 3003, 2984, 2969, 2958, 2935, 1741, 1658, 159
9, 1555, 1428, 1226, 1216, 1158, 1102;1H NMR (300 MHz, CDClThree) 1.00 (t
, J = 7.3 Hz, 3 H), 1.44 (s, 9 H), 1.84 (m, 2 H), 3.75 (s, 1 H), 4.21 (d
, J = 5.7 Hz, 2 H), 5.19 (d, J = 16.3 Hz, 1 H), 5.64 (d, J = 16.3 Hz, 1
H), 7.43 (m, 5 H), 7.51 (t, J = 7.3 Hz, 2 H), 7.62 (s, 1 H), 7.69 (m, 5
H), 8.10 (d, J = 8.5 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 1 H);13C NMR (75 M
Hz, CDClThree) 7.9, 20.4, 30.2, 31.6, 52.2, 66.4, 72.8, 97.5, 118.2, 126.3,
128.6, 129.8, 130.3, 130.7, 131.9, 132.2, 134.6, 134.64, 136.4, 136.5,
138.1, 140.9, 146.2, 148.4, 149.9, 151.3, 157.1, 174.1; C36H34NTwoOFourSi (M + HRMS (EI) m / z 586.2281, found 586.2288; LRMS (EI) m / z
586 (M+), 542, 529, 485, 428, 407, 321, 181, 131, 69.Example 4 Production of (20S) -10-acetoxy-7-trimethylsilylcamptothecin (see FIG. 3)
【００４１】 [0041]
【００４２】 (1) 4-アセトキシフェニル イソニトリル (14) 4-アセトキシホルムアミド (13) (358 mg, 1.0 mmol)のCH2Cl2 (10 mL)溶液に
、 0℃下、テトラブロモメタン (0.70 g, 2.1 mmol)、トリフェニルホスフィン
(525 mg, 2.1 mmol)及びトリエチルアミン (320 mL, 2.1 mmol)を連続的に添加 し、得られた混合物を暗中で3時間還流した。溶媒を蒸発させた後、粗生成物を 氷冷Et2O (20 mL)中で摩砕し、ろ過した。溶媒を蒸発させ、残渣をフラッシュク
ロマトグラフィー (ヘキサン/AcOEt 8:2)により精製し、243 mg (76%)のわずか に褐色の固体を得た: IR (ニート, cm-1) 2127, 1768, 1501, 1370, 1201, 118
0, 909; 1H NMR (300 MHz, CDCl3) 2.29 (s, 3 H), 7.11 (d, J = 8.8 Hz, 2
H), 7.38 (d, J = 8.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) 21.0, 122.8, 12
7.6, 150.8, 164.3, 168.8; C9H7NO2 (M+) について計算したHRMS (EI) m/z 16
1.0477,実測値161.0474; LRMS (EI) m/z 161 (M+), 133, 119, 91.(1) 4-Acetoxyphenyl isonitrile (14) A solution of 4-acetoxyformamide (13) (358 mg, 1.0 mmol) in CH 2 Cl 2 (10 mL) was added with tetrabromomethane (0.70 g) at 0 ° C. , 2.1 mmol), triphenylphosphine
(525 mg, 2.1 mmol) and triethylamine (320 mL, 2.1 mmol) were added successively, and the resulting mixture was refluxed in the dark for 3 hours. After evaporation of the solvent, the crude product was triturated in ice-cold Et 2 O (20 mL), and filtered. The solvent was evaporated and the residue was purified by flash chromatography (hexane / AcOEt 8: 2) to give 243 mg (76%) of a slightly brown solid: IR (neat, cm- 1 ) 2127, 1768, 1501, 1370, 1201, 118
0, 909; 1 H NMR (300 MHz, CDCl 3 ) 2.29 (s, 3 H), 7.11 (d, J = 8.8 Hz, 2
H), 7.38 (d, J = 8.8 Hz, 2 H); 13 C NMR (75 MHz, CDCl 3 ) 21.0, 122.8, 12
7.6, 150.8, 164.3, 168.8; HRMS (EI) m / z 16 calculated for C 9 H 7 NO 2 (M + )
1.0477, found 161.0474; LRMS (EI) m / z 161 (M + ), 133, 119, 91.
【００４３】 (2) (20S)-10-アセトキシ-7-トリメチルシリルカンプトテシン (15) 実施例1-(2)に記載の手順に従い、実施例1-(1)で製造した化合物(44.5 mg, 0.
10 mmol)及び (1)で製造した化合物(48.3 mg, 0.30 mmol)を提供し、フラッシュ
クロマトグラフィー (CHCl3/アセトン 10:1)後に、29.9 mg(63%)のわずかに黄色
の油を得た: []20 D +29.9 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) 0.61
(s, 9 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.86 (m, 2 H), 2.38 (s, 3 H), 4.13
(br s, 1 H), 5.24 (d, J = 16.4 Hz, 1 H), 5.27 (s, 2 H), 5.68 (d, J = 16
.4 Hz, 1 H), 7.46 (dd, J = 9.2, 2.5 Hz, 1 H), 7.60 (s, 1 H), 7.96 (d, J
= 2.5 Hz, 1 H), 8.13 (d, J = 9.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) 1.
4, 7.8, 21.4, 31.5, 51.7, 66.2, 97.6, 118.3, 118.9, 124.6, 132.1, 135.0,
145.7, 146.1, 148.9, 150.1, 150.7, 157.3, 169.1, 173.7; C25H26N2O6Si (
M+) について計算したHRMS (EI) m/z 478.1560,実測値478.1582; LRMS (EI) m/
z 478 (M+), 436, 392, 377, 336, 277. 実施例5 (20S)-10-ヒドロキシ-7-トリメチルシリルカンプトテシン(16) の製造(2) (20S) -10-acetoxy-7-trimethylsilylcamptothecin (15) According to the procedure described in Example 1- (2), the compound prepared in Example 1- (1) (44.5 mg, 0 .
10 mmol) and the compound prepared in (1) (48.3 mg, 0.30 mmol) were obtained and after flash chromatography (CHCl 3 / acetone 10: 1) 29.9 mg (63%) of a slightly yellow oil were obtained. T: [] 20 D +29.9 (c 0.5, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) 0.61
(s, 9 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.86 (m, 2 H), 2.38 (s, 3 H), 4.13
(br s, 1 H), 5.24 (d, J = 16.4 Hz, 1 H), 5.27 (s, 2 H), 5.68 (d, J = 16
.4 Hz, 1 H), 7.46 (dd, J = 9.2, 2.5 Hz, 1 H), 7.60 (s, 1 H), 7.96 (d, J
= 2.5 Hz, 1 H), 8.13 (d, J = 9.2 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 1.
4, 7.8, 21.4, 31.5, 51.7, 66.2, 97.6, 118.3, 118.9, 124.6, 132.1, 135.0,
145.7, 146.1, 148.9, 150.1, 150.7, 157.3, 169.1, 173.7; C 25 H 26 N 2 O 6 Si (
M +) HRMS calculated for (EI) m / z 478.1560, Found 478.1582; LRMS (EI) m /
z 478 (M + ), 436, 392, 377, 336, 277.Example 5 Production of (20S) -10-hydroxy-7-trimethylsilylcamptothecin (16)
【００４４】 [0044]
【００４５】 MeOH (100 mL)及びH2O (100 mL)中の実施例5-(2)で製造した化合物(15)(16.8
mg, 0.035 mmol)及びK2CO3 (9.6 mg, 0.070 mmol)の溶液を、室温下で1時間30分
攪拌した。反応混合物をAcOH (2滴)で酸性化し、塩水(10 mL)で希釈し、AcOEt (
10 x 10 mL)で抽出した。組み合わせた有機層を乾燥し(Na2SO4)、蒸発させ、残 渣をフラッシュクロマトグラフィー (CHCl3/MeOH/AcOH 90:10:2; CHCl3/アセト ン 2:1)により精製し、15.1 mg (99%)の白色固体を得た: []20 D +18.9 (c 0.2,
CHCl3/MeOH 4:1); 1H NMR (300 MHz, CDCl3/CD3OD 4:1) 0.45 (s, 9 H), 0.8
4 (t, J = 7.3 Hz, 3 H), 1.75 (m, 2 H), 5.12 (br s, 2 H), 5.12 (d, J = 1
6.3 Hz, 1 H), 5.48 (d, J = 16.3 Hz, 1 H), 7.24 (dd, J = 9.1, 2.5 Hz, 1 H
), 7.39 (d, J = 2.5 Hz, 1 H), 7.87 (d, J = 9.1 Hz, 1 H); 13C NMR (75 MH
z, CDCl3/CD3OD 4:1) 0.8, 7.4, 31.1, 51.8, 65.7, 97.5, 109.8, 117.5, 122
.3, 131.3, 133.7, 134.6, 141.7, 142.6, 146.3, 147.5, 151.1, 156.3, 157.6
; C23H24N2O5Si (M+) について計算したHRMS (EI) m/z 436.1454,実測値436.14
50; LRMS (EI) m/z 436 (M+), 392, 377, 336, 323. この化合物とNH2CH2CH2NMe2 との反応、続いてEtCOClとの反応により、生物学
的試験用の開環E−環類似体を得た。 実施例6 (20S)7-トリメチルシリル-イリノテカン(図6参照)の製造Compound (15) (16.8) prepared in Example 5- (2) in MeOH (100 mL) and H 2 O (100 mL)
mg, 0.035 mmol) and K 2 CO 3 (9.6 mg, 0.070 mmol) were stirred at room temperature for 1 hour 30 minutes. The reaction mixture was acidified with AcOH (2 drops), diluted with brine (10 mL) and extracted with AcOEt (
(10 x 10 mL). The combined organic layers were dried (Na 2 SO 4 ), evaporated and the residue was purified by flash chromatography (CHCl 3 / MeOH / AcOH 90: 10: 2; CHCl 3 / acetone 2: 1) to give 15.1 mg (99%) of a white solid: [] 20 D +18.9 (c 0.2,
CHCl 3 / MeOH 4: 1); 1 H NMR (300 MHz, CDCl 3 / CD 3 OD 4: 1) 0.45 (s, 9 H), 0.8
4 (t, J = 7.3 Hz, 3 H), 1.75 (m, 2 H), 5.12 (br s, 2 H), 5.12 (d, J = 1
6.3 Hz, 1 H), 5.48 (d, J = 16.3 Hz, 1 H), 7.24 (dd, J = 9.1, 2.5 Hz, 1 H
), 7.39 (d, J = 2.5 Hz, 1 H), 7.87 (d, J = 9.1 Hz, 1 H); 13 C NMR (75 MH
z, CDCl 3 / CD 3 OD 4: 1) 0.8, 7.4, 31.1, 51.8, 65.7, 97.5, 109.8, 117.5, 122
.3, 131.3, 133.7, 134.6, 141.7, 142.6, 146.3, 147.5, 151.1, 156.3, 157.6
; C 23 H 24 N 2 O 5 Si (M +) for calculated HRMS (EI) m / z 436.1454 , Found 436.14
50; LRMS (EI) m / z 436 (M + ), 392, 377, 336, 323. Biological testing by reaction of this compound with NH 2 CH 2 CH 2 NMe 2 followed by EtCOCl Opened E-ring analog was obtained. Example 6 Production of (20S) 7-trimethylsilyl-irinotecan (see FIG. 6)
【００４６】 [0046]
【００４７】 (1) [1,4'] ビピペリジニル-1'-カルボン酸 4-ニトロ-フェニルエステル (32) 4-ニトロフェニル クロロホルマート (31) (5.15 g, 25.6 mmol)の150 mL乾燥
THF溶液に、-78℃下、トリエチルアミン (10.7 mL, 76.2 mmol)を添加し、続い て4-ピペリジノピペリジン(30)(4.51 g, 25.6 mmol)の40mL THF溶液を添加した 。この溶液を2時間攪拌し、その後溶媒を除去し、残渣をAcOEt中に集め、ろ過し
、蒸発させた。粗い黄色の固体を、溶離剤としてAcOEtを使用し、中性アルミナ のパッドを通過させ、蒸発後に6.73 g (79%)の白色固体を得た: IR (CHCl3, cm -1 ) 3046, 2937, 2859, 1704, 1620, 1513, 1466, 1242, 1197; 1H NMR (300 M
Hz, CDCl3) 1.20-1.80 (m, 8 H), 1.90 (d, J = 12.7 Hz, 2 H), 2.20-2.70 (m
, 5 H), 2.87 (t, J = 12 Hz, 1 H), 3.01 (t, J = 12 Hz, 1 H), 4.30 (br s,
2 H), 7.29 (d, J = 9 Hz, 2 H), 8.26 (d, J = 9 Hz, 2 H); 13C NMR (75 MHz
, CDCl3) 24.6, 26.3, 27.5, 28.2, 40.1, 44.4, 50.1, 62.0, 122.2, 124.9,
144.8, 151.9, 156.3; C17H23N3O4 (M+) について計算したHRMS (EI) m/z 333.
1676,実測値333.1688; LRMS (EI) m/z 333 (M+), 195, 167, 124, 110, 96, 55
.(1) [1,4 ′] Bipiperidinyl-1′-carboxylic acid 4-nitro-phenyl ester (32) 4-nitrophenyl chloroformate (31) (5.15 g, 25.6 mmol) dried in 150 mL
To the THF solution was added triethylamine (10.7 mL, 76.2 mmol) at −78 ° C., followed by a solution of 4-piperidinopiperidine (30) (4.51 g, 25.6 mmol) in 40 mL THF. The solution was stirred for 2 hours, after which the solvent was removed and the residue was collected in AcOEt, filtered.
And evaporated. The crude yellow solid was passed through a pad of neutral alumina using AcOEt as eluent to give 6.73 g (79%) of a white solid after evaporation: IR (CHClThree, cm -1 ) 3046, 2937, 2859, 1704, 1620, 1513, 1466, 1242, 1197;1H NMR (300 M
Hz, CDClThree) 1.20-1.80 (m, 8 H), 1.90 (d, J = 12.7 Hz, 2 H), 2.20-2.70 (m
, 5 H), 2.87 (t, J = 12 Hz, 1 H), 3.01 (t, J = 12 Hz, 1 H), 4.30 (br s,
2H), 7.29 (d, J = 9 Hz, 2 H), 8.26 (d, J = 9 Hz, 2 H);13C NMR (75 MHz
, CDClThree) 24.6, 26.3, 27.5, 28.2, 40.1, 44.4, 50.1, 62.0, 122.2, 124.9,
144.8, 151.9, 156.3; C17Htwenty threeNThreeOFour (M+HRMS (EI) m / z 333 calculated for).
1676, found 333.1688; LRMS (EI) m / z 333 (M+), 195, 167, 124, 110, 96, 55
.
【００４８】 (2) [1,4'] ビピペリジニル-1'-カルボン酸 4-アミノ-フェニルエステル (1)で製造した化合物(1.012 g, 3.03 mmol)のAcOEt (125 ml)溶液に、10% Pd/
C (0.15 g)を添加した。系をアルゴンで数回パージし、H2の1 L バルーンを添加
した。得られた混合物を室温下で12時間攪拌した後、触媒をセライト（celite）
を通したろ過により除去し、溶媒を蒸発させ、835 mg (91%)の白色固体を得た:
IR (CHCl3, cm-1) 3453, 3400, 3028, 2936, 2859, 1703, 1513, 1429, 1242,
1226, 1210, 1197; 1H NMR (300 MHz, CDCl3) 1.30-1.70 (m, 8 H), 1.86 (d,
J = 12.6 Hz, 2 H), 2.33-2.62 (m, 5 H), 2.68-3.04 (m, 2 H), 3.58 (br s,
2 H), 4.30 (br s, 2 H), 6.64 (d, J = 6.0 Hz, 2 H), 6.87 (d, J = 6.0 Hz,
2 H); 13C NMR (75 MHz, CDCl3) 24.6, 26.3, 27.5, 28.1, 43.8, 43.9, 50.1
, 62.3, 115.4, 122.3, 143.4, 143.7, 154.1; C17H25N3O2 (M+) について計算
したHRMS (EI) m/z 303.1944 ,実測値303.1947; LRMS (EI) m/z 303 (M+), 195
, 167, 124, 108, 96, 80, 65, 55.(2) 10% was added to a solution (1.012 g, 3.03 mmol) of the compound (1.012 g, 3.03 mmol) prepared in [1,4 ′] bipiperidinyl-1′-carboxylic acid 4-amino-phenyl ester (1) in AcOEt (125 ml). Pd /
C (0.15 g) was added. The system was purged with argon several times, it was added 1 L balloon H 2. After the resulting mixture was stirred at room temperature for 12 hours, the catalyst was removed from celite.
Filtration through and evaporation of the solvent gave 835 mg (91%) of a white solid:
IR (CHCl 3 , cm -1 ) 3453, 3400, 3028, 2936, 2859, 1703, 1513, 1429, 1242,
1226, 1210, 1197; 1 H NMR (300 MHz, CDCl 3 ) 1.30-1.70 (m, 8 H), 1.86 (d,
J = 12.6 Hz, 2 H), 2.33-2.62 (m, 5 H), 2.68-3.04 (m, 2 H), 3.58 (br s,
2 H), 4.30 (br s, 2 H), 6.64 (d, J = 6.0 Hz, 2 H), 6.87 (d, J = 6.0 Hz,
2 H); 13 C NMR (75 MHz, CDCl 3 ) 24.6, 26.3, 27.5, 28.1, 43.8, 43.9, 50.1
, 62.3, 115.4, 122.3, 143.4 , 143.7, 154.1; C 17 H 25 N 3 O 2 (M +) HRMS calculated for (EI) m / z 303.1944, Found 303.1947; LRMS (EI) m / z 303 ( M + ), 195
, 167, 124, 108, 96, 80, 65, 55.
【００４９】 (3) [1,4'] ビピペリジニル-1'-カルボン酸 4-ホルミルアミノ-フェニルエステ ル (33) ジシクロヘキシルカルボジイミド (272 mg, 1.32 mmol)のCH2Cl2 (5 mL)溶液 に攪拌しながら、0℃下、98% ギ酸 (60.7 mg, 1.32 mmol)を滴下した。10 分後 、得られた混合物を、実施例 (2)で製造した化合物(200 mg, 0.66 mmol)の in ピリジン (5 mL)溶液に、シリンジを介して0℃下で添加した。次いで反応混合物
を室温まで暖め、3時間攪拌した。ピリジン溶媒を蒸発させ、残渣をCH2Cl2中に 集め、ろ過し、蒸発させ、塩基性アルミナカラム(CH2Cl2/MeOH 95:5)に直接付し
、118 mg (83%)の白色固体を得た。これは、室温下で、ホルムアミドの炭素−窒
素結合周囲の回転障害に由来するシス及びトランス回転異性体の混合物から構成
されていた: IR (CHCl3, cm-1) 3025, 3013, 2937, 2888, 2861, 1703, 1517,
1466, 1275, 1226, 1210; 1H NMR (300 MHz, CDCl3) 1.38-1.80 (m, 8 H), 1.
90 (d, J = 12 Hz, 2 H), 2.40-2.70 (m, 5 H), 2.83 (t, J = 12 Hz, 1 H), 2.
97 (t, J = 12 Hz, 1 H), 4.32 (m, 2 H), 7.03-7.11 (m, 3 H), 7.37 (br s, .
5 H) (シス), 7.46 (d, J = 10 Hz, 1 H), 7.53 (d, J = 11 Hz, .5 H) (トラン
ス), 8.32 (d, J = 2 Hz, .5 H) (シス), 8.59 (d, J = 11 Hz, .5 H) (トラン ス); 13C NMR (75 MHz, CDCl3) 24.6, 26.3, 27.6, 28.1, 44.2, 44.0, 50.1,
82.2, 120.0, 121.0, 122.1, 123.0, 133.9, 134.3, 147.5, 148.9, 153.9, 15
3.4, 159.1, 162.5; C18H25N3O3 (M+) について計算したHRMS (EI) m/z 331.18
84,実測値331.1896; LRMS (EI) m/z 331 (M+), 244, 202, 167, 124, 80, 55.(3) [1,4 ′] Bipiperidinyl-1′-carboxylic acid 4-formylamino-phenylester (33) Dicyclohexylcarbodiimide (272 mg, 1.32 mmol) was added to a CH 2 Cl 2 (5 mL) solution. Under stirring, 98% formic acid (60.7 mg, 1.32 mmol) was added dropwise at 0 ° C. After 10 minutes, the obtained mixture was added to a solution of the compound prepared in Example (2) (200 mg, 0.66 mmol) in pyridine (5 mL) at 0 ° C via a syringe. The reaction mixture was then warmed to room temperature and stirred for 3 hours. Pyridine solvent was evaporated and the residue collected in CH 2 Cl 2, filtered and evaporated to basic alumina column (CH 2 Cl 2 / MeOH 95 : 5) to directly subjected, 118 white mg (83%) A solid was obtained. It consisted, at room temperature, of a mixture of cis and trans rotamers resulting from rotational hindrance around the carbon-nitrogen bond of formamide: IR (CHCl 3 , cm −1 ) 3025, 3013, 2937, 2888 , 2861, 1703, 1517,
1466, 1275, 1226, 1210; 1 H NMR (300 MHz, CDCl 3 ) 1.38-1.80 (m, 8 H), 1.
90 (d, J = 12 Hz, 2 H), 2.40-2.70 (m, 5 H), 2.83 (t, J = 12 Hz, 1 H), 2.
97 (t, J = 12 Hz, 1 H), 4.32 (m, 2 H), 7.03-7.11 (m, 3 H), 7.37 (br s,.
5H) (cis), 7.46 (d, J = 10 Hz, 1 H), 7.53 (d, J = 11 Hz, .5 H) (trans), 8.32 (d, J = 2 Hz, .5 H) (Cis), 8.59 (d, J = 11 Hz, .5 H) (trans); 13 C NMR (75 MHz, CDCl 3 ) 24.6, 26.3, 27.6, 28.1, 44.2, 44.0, 50.1,
82.2, 120.0, 121.0, 122.1, 123.0, 133.9, 134.3, 147.5, 148.9, 153.9, 15
3.4, 159.1, 162.5; C 18 H 25 N 3 O 3 (M +) HRMS calculated for (EI) m / z 331.18
84, found 331.1896; LRMS (EI) m / z 331 (M + ), 244, 202, 167, 124, 80, 55.
【００５０】 (4) [1,4'] ビピペリジニル-1'-カルボン酸 4-イソニトリロ-フェニルエステル
(34) 実施例 (3)で製造した化合物 (90.1 mg, 0.272 mmol)のCH2Cl2 (10 mL)溶液に
、連続的にトリエチルアミン (69.5 mg, 0.688 mmol)を滴下し、0℃下、トリホ スゲン(68 mg, 0.229 mmol)の乾燥CH2Cl2 (10 mL)溶液を添加した。混合物を室 温下で2時間攪拌し、7% NaHCO3 (5 mL)で洗浄し、乾燥(MgSO4)した。溶媒の蒸発
後に得られた粗い褐色の残渣をフラッシュクロマトグラフィー (Et2O/Et2NH 95:
5)に付し、67.2 mg (79%)の白色固体を得た: IR (CHCl3, cm-1) 3034, 2937, 2
131, 1718, 1504, 1429, 1233, 1224, 1213, 1198, 1184; 1H NMR (300 MHz, C
DCl3) 1.32-1.75 (m, 8 H), 1.90 (br d, J = 12.4 Hz, 2 H), 2.32-2.65 (m,
5 H), 2.84 (t, J = 12.3 Hz, 1 H), 2.98 (t, J = 12.1 Hz, 1 H), 4.20-4.40
(m, 2 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2 H); 13C NMR
(75 MHz, CDCl3) 25.0, 26.5, 27.8, 28.5, 44.4, 50.6, 62.7, 123.3, 127.8
, 152.1, 153.1, 164.4; C18H23N3O2 (M+) について計算したHRMS (EI) m/z 31
3.1779,実測値313.1790; LRMS (EI) m/z 313 (M+), 195, 167, 124 ,110, 84,
55.(4) [1,4 ′] Bipiperidinyl-1′-carboxylic acid 4-isonitrile-phenyl ester
(34) Triethylamine (69.5 mg, 0.688 mmol) was continuously added dropwise to a solution of the compound (90.1 mg, 0.272 mmol) produced in Example (3) in CH 2 Cl 2 (10 mL), and the mixture was added at 0 ° C. A solution of triphosgene (68 mg, 0.229 mmol) in dry CH 2 Cl 2 (10 mL) was added. The mixture was stirred at room temperature for 2 hours, washed with 7% NaHCO 3 (5 mL) and dried (MgSO 4 ). The crude brown residue obtained after evaporation of the solvent was flash-chromatographed (Et 2 O / Et 2 NH 95:
5) to give 67.2 mg (79%) of a white solid: IR (CHCl 3 , cm −1 ) 3034, 2937, 2
131, 1718, 1504, 1429, 1233, 1224, 1213, 1198, 1184; 1 H NMR (300 MHz, C
DCl 3 ) 1.32-1.75 (m, 8 H), 1.90 (br d, J = 12.4 Hz, 2 H), 2.32-2.65 (m,
5H), 2.84 (t, J = 12.3 Hz, 1 H), 2.98 (t, J = 12.1 Hz, 1 H), 4.20-4.40
(m, 2 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2 H); 13 C NMR
(75 MHz, CDCl 3 ) 25.0, 26.5, 27.8, 28.5, 44.4, 50.6, 62.7, 123.3, 127.8
, HRMS (EI) m / z 31 calculated for C 18 H 23 N 3 O 2 (M + ), 152.1, 153.1, 164.4;
3.1779, found 313.1790; LRMS (EI) m / z 313 (M + ), 195, 167, 124, 110, 84,
55.
【００５１】 (5) (20S)-7-トリメチルシリル-イリノテカン (35) 実施例1-(2)に記載の手順に従い、実施例1-(1)で製造した化合物(44.5 mg, 0.
10 mmol)、(4)で製造した化合物(93.9 mg,0.3 mmol)及びヘキサメチルジチン(50
mg, 0.15 mmol)を乾燥ベンゼン(1.5 mL)中、275W GEサンランプを用いて、70℃
で9時間照射した。反応物を蒸発させ、溶解性を補助するために数滴のDMSOを用 いてMeOH中に溶解し、ウォーターズ逆相HPLCへ注入した。分離を行うために使用
した条件は以下の通りであった。ウォーターズ490Eプログラマブル多波長検出器
を備えたウォーターズ600Eシステムコントローラー 、サージェント ウェルチ （Sargent Welch）プロッター及びウォーターズC-18 25x10カートリッジカラム を使用した。勾配溶離 [ 5:95 MeCN/H2O (0.1% TFA)〜30:70 MeCN/H2O (0.1% TF
A)]を20 mL/分で40 分間行い、凍結乾燥後に半精製された灰色の固体を得た。灰
色の固体を、1 mm を使用したクロマトトロン（chromatotron）中で更に精製(CH 2 Cl2/EtOH 70:30)し、12 mg (19%)の黄色の固体を得た: []20 D +14.8 (c 0.2, C
HCl3); IR (CHCl3, cm-1) 3023, 2957, 2933, 1720, 1659, 1601, 1216, 1191,
1175, 1158; 1H NMR (300 MHz, CDCl3) 0.64 (s, 9 H), 1.03 (t, J = 7.3 Hz
, 3 H), 1.50-1.51 (br m, 2 H), 1.51-1.52 (br m, 6 H), 1.84 (m, J = 7.3 H
z, 2 H), 2.01- 2.10 (br m, 2 H), 2.60-2.75 (br s, 5 H), 2.75-3.12 (br m,
2 H), 4.30-4.50 (br m, 2 H), 5.30 (d, J = 16.3 Hz, 1 H), 5.31 (s, 2 H),
5.74 (d, J = 16.3 Hz, 1 H), 7.55 (dd, J = 9.0, 2.4 Hz, 1 H), 7.63 (s, 1
H), 8.01 (d, J = 2.3 Hz, 1 H), 8.19 (d, J = 9 Hz, 1 H); 13C NMR (75 MH
z, CDCl3) 1.5, 7.8, 25.4, 29.7, 31.5, 43.8, 50.1, 51.8, 62.5, 66.3, 72.
8, 97.5, 118.1, 119.0, 125.1, 132.0, 132.3, 134.9, 143.4, 145.6, 146.4,
150.1, 150.5, 152.8, 157.4, 174.0; C34H42N4O6Si (M+) について計算したHR
MS (EI) m/z 630.2898,実測値630.2874; LRMS (EI) m/z 630 (M+), 586, 501,
457, 195, 167, 153, 124, 111, 96, 84. 実施例7 (20S)-11-フルオロ-7-トリメチルシリルカンプトテシンの製造(図2参照)(5) (20S) -7-Trimethylsilyl-irinotecan (35) According to the procedure described in Example 1- (2), the compound produced in Example 1- (1) (44.5 mg, 0.2%).
10 mmol), the compound prepared in (4) (93.9 mg, 0.3 mmol) and hexamethylditin (50
mg, 0.15 mmol) in dry benzene (1.5 mL) using a 275W GE sunlamp at 70 ° C.
For 9 hours. The reaction was evaporated, dissolved in MeOH with a few drops of DMSO to aid solubility and injected into a Waters reverse phase HPLC. Used to perform separation
The conditions performed were as follows. Waters 490E programmable multi-wavelength detector
Waters 600E System Controller with Waters, Sargent Welch Plotter and Waters C-18 25xTenA cartridge column was used. Gradient elution [5:95 MeCN / HTwoO (0.1% TFA) to 30:70 MeCN / HTwoO (0.1% TF
A)] was performed at 20 mL / min for 40 minutes to obtain a semi-purified gray solid after lyophilization. Ash
The color solid is further purified in a chromatotron using 1 mm (CH Two ClTwo/ EtOH 70:30) to give 12 mg (19%) of a yellow solid: []20 D +14.8 (c 0.2, C
HClThree); IR (CHClThree, cm-1) 3023, 2957, 2933, 1720, 1659, 1601, 1216, 1191,
1175, 1158;1H NMR (300 MHz, CDClThree) 0.64 (s, 9 H), 1.03 (t, J = 7.3 Hz
, 3 H), 1.50-1.51 (br m, 2 H), 1.51-1.52 (br m, 6 H), 1.84 (m, J = 7.3 H
z, 2 H), 2.01- 2.10 (br m, 2 H), 2.60-2.75 (br s, 5 H), 2.75-3.12 (br m,
2 H), 4.30-4.50 (br m, 2 H), 5.30 (d, J = 16.3 Hz, 1 H), 5.31 (s, 2 H),
5.74 (d, J = 16.3 Hz, 1 H), 7.55 (dd, J = 9.0, 2.4 Hz, 1 H), 7.63 (s, 1
H), 8.01 (d, J = 2.3 Hz, 1 H), 8.19 (d, J = 9 Hz, 1 H);13C NMR (75 MH
z, CDClThree) 1.5, 7.8, 25.4, 29.7, 31.5, 43.8, 50.1, 51.8, 62.5, 66.3, 72.
8, 97.5, 118.1, 119.0, 125.1, 132.0, 132.3, 134.9, 143.4, 145.6, 146.4,
150.1, 150.5, 152.8, 157.4, 174.0; C34H42NFourO6Si (M+HR calculated for)
MS (EI) m / z 630.2898, found 630.2874; LRMS (EI) m / z 630 (M+), 586, 501,
457, 195, 167, 153, 124, 111, 96, 84.Example 7 Production of (20S) -11-fluoro-7-trimethylsilylcamptothecin (see FIG. 2)
【００５２】 [0052]
【００５３】 (1) 3-フルオロ-2-トリメチルシリルベンズアルデヒド (7) 3-フルオロ-2-トリメチルシリルベンズアルデヒドの製造を、選択的オルトメ タル化により進めた。Comins, D. L. et al., J. Org. Chem., 49, 1078 (1984)
を参照のこと。更にSnieckus, V., Chem. Rev., 90, 879 (1990)も参照のこと。
N,N,N'-トリメチルエチレンジアミン (2.70 mL, 20 mmol)のTHF (50 mL)溶液に 、1.6 N n-BuLiのヘキサン (13 mL, 21 mmol)溶液を-20℃下でゆっくりと添加し
、続いて15分後に3-フルオロベンズアルデヒド (2.10 mL, 20 mmol)を添加した 。この温度で15 分後、1.6 N n-BuLiのヘキサン (38 mL, 60 mmol)溶液を注入し
、溶液を-35℃で1時間30分攪拌した。クロロトリメチルシラン (15 mL, 120 mmo
l)を添加し、反応混合物を室温下で一晩攪拌した。最終の溶液を氷冷1 N HCl (1
50 mL)へ注ぎ、Et2O (3 x 100)で迅速に抽出し、塩水で洗浄し、乾燥 (Na2SO4) した。溶媒を蒸発させた後、残渣をフラッシュクロマトグラフィー (ヘキサン/A
cOEt 95:5)により精製し、3.25 g (83%)の油を得た: IR (ニート, cm-1) 1701,
1440, 1252, 1233, 1109, 848, 764; 1H NMR (300 MHz, CDCl3) 0.40 (d, J
= 2.6 Hz, 9 H), 7.18 (br t, J = 9.0 Hz, 1 H), 7.47 (ddd, J1 = J2 = 8.1 H
z, J3 = 5.4 Hz, 1 H), 7.70 (br d, J = 7.5 Hz, 1 H); 13C NMR (75 MHz, CD
Cl3) 1.8, 120.8 (d, JCF = 29 Hz), 126.8, 128.2, 131.2, 143.3, 167.6 (d,
JCF = 244 Hz), 192.4; C9H10FOSi (M-CH3 +) について計算したHRMS (EI) m/z
181.0485,実測値181.0482; LRMS (EI) m/z 181 (M-CH3 +), 151, 125, 103, 91
.(1) 3-Fluoro-2-trimethylsilylbenzaldehyde (7) The production of 3-fluoro-2-trimethylsilylbenzaldehyde proceeded by selective orthometalation. Comins, DL et al., J. Org.Chem., 49, 1078 (1984).
checking ... See also Snieckus, V., Chem. Rev., 90, 879 (1990).
To a solution of N, N, N'-trimethylethylenediamine (2.70 mL, 20 mmol) in THF (50 mL) was slowly added a 1.6 N n-BuLi solution in hexane (13 mL, 21 mmol) at -20 ° C. After 15 minutes, 3-fluorobenzaldehyde (2.10 mL, 20 mmol) was added. After 15 minutes at this temperature, a 1.6 N n-BuLi hexane (38 mL, 60 mmol) solution was injected and the solution was stirred at -35 ° C for 1 hour 30 minutes. Chlorotrimethylsilane (15 mL, 120 mmo
l) was added and the reaction mixture was stirred overnight at room temperature. The final solution is ice-cold 1 N HCl (1
50 mL), quickly extracted with Et 2 O (3 × 100), washed with brine and dried (Na 2 SO 4 ). After evaporation of the solvent, the residue is flash chromatographed (hexane / A
Purification by cOEt 95: 5) gave 3.25 g (83%) of an oil: IR (neat, cm -1 ) 1701,
1440, 1252, 1233, 1109, 848, 764; 1 H NMR (300 MHz, CDCl 3 ) 0.40 (d, J
= 2.6 Hz, 9 H), 7.18 (br t, J = 9.0 Hz, 1 H), 7.47 (ddd, J 1 = J 2 = 8.1 H
z, J 3 = 5.4 Hz, 1 H), 7.70 (br d, J = 7.5 Hz, 1 H); 13 C NMR (75 MHz, CD
Cl 3 ) 1.8, 120.8 (d, J CF = 29 Hz), 126.8, 128.2, 131.2, 143.3, 167.6 (d,
J CF = 244 Hz), 192.4; HRMS (EI) m / z calculated for C 9 H 10 FOSi (M-CH 3 + )
181.0485, observed 181.0482; LRMS (EI) m / z 181 (M-CH 3 + ), 151, 125, 103, 91
.
【００５４】 (2) 3-フルオロ-2-トリメチルシリル安息香酸 次いで遊離酸の古典的酸化を行った。Hill, L. R. et al., J. Org. Chem., 5
0, 470 (1985)を参照のこと。(1)で製造した化合物 (3.41 g, 17.3 mmol)のtert
-ブタノール (20 mL)溶液に、2N 2-メチル-2-ブテンのTHF (55 mL, 110 mmol)溶
液を添加し、次いでゆっくりと10 分間かけて、80% NaClO2 (2.55 g, 22.5 mmol
) 及びNaH2PO4.H2O (3.10 g, 22.5 mmol)の水溶液(18 mL)を連続的に添加した。
得られた混合物を室温下で16時間攪拌し、tert-ブタノールを蒸発させ、残渣を1
N NaOH (50 mL)中に集め、ヘキサン (3 x 20 mL)で洗浄した。水性層 を1N HCl
でpH 2まで酸性化し、NaClで飽和し、Et2O (3 x 50 mL)で抽出した。組み合わせ
た有機層を乾燥(Na2SO4)し、蒸発し、3.13 g (85%)の白色固体を得た: IR (NaC
l, cm-1) 2982, 1700, 1434, 1294, 1271, 1253, 1230, 849, 763; 1H NMR (30
0 MHz, CDCl3) 0.39 (d, J = 2.6 Hz, 9 H), 7.16 (br t, J = 9.1 Hz, 1 H),
7.41 (ddd, J1 = J2 = 7.9 Hz, J3 = 5.6 Hz, 1 H), 7.73 (br d, J = 7.7 Hz,
1 H); 13C NMR (75 MHz, CDCl3) 1.3, 119.5 (d, JCF = 27 Hz), 126.0, 127.
3, 130.9, 138.0, 167.5 (d, JCF = 243 Hz), 174.5; C9H10FO2Si (M-CH3 +) に
ついて計算したHRMS (EI) m/z 197.0434,実測値197.0433; LRMS (EI) m/z 197
(M-CH3 +), 179, 133, 115, 105.(2) 3-Fluoro-2-trimethylsilylbenzoic acid The classical oxidation of the free acid was then performed. Hill, LR et al., J. Org. Chem., 5
See 0, 470 (1985). Compound (3.41 g, 17.3 mmol) produced in (1) tert
To a solution of 2N 2-methyl-2-butene in THF (55 mL, 110 mmol) was added to a solution of 2-N-methyl-2-butene in THF (55 mL, 110 mmol), and then slowly over 10 minutes, 80% NaClO 2 (2.55 g, 22.5 mmol
) And NaH 2 PO 4 .H 2 O ( 3.10 g, was added an aqueous solution of 22.5 mmol) of (18 mL) successively.
The resulting mixture was stirred at room temperature for 16 hours, tert-butanol was evaporated and the residue was
Collected in N NaOH (50 mL) and washed with hexane (3 x 20 mL). Aqueous layer with 1N HCl
In acidified to pH 2, saturated with NaCl, and extracted with Et 2 O (3 x 50 mL ). The combined organic layers were dried (Na 2 SO 4 ) and evaporated to give 3.13 g (85%) of a white solid: IR (NaC
l, cm -1 ) 2982, 1700, 1434, 1294, 1271, 1253, 1230, 849, 763; 1 H NMR (30
0 MHz, CDCl 3 ) 0.39 (d, J = 2.6 Hz, 9 H), 7.16 (br t, J = 9.1 Hz, 1 H),
7.41 (ddd, J 1 = J 2 = 7.9 Hz, J 3 = 5.6 Hz, 1 H), 7.73 (br d, J = 7.7 Hz,
1 H); 13 C NMR (75 MHz, CDCl 3 ) 1.3, 119.5 (d, J CF = 27 Hz), 126.0, 127.
3, 130.9, 138.0, 167.5 (d, J CF = 243 Hz), 174.5; HRMS (EI) m / z calculated for C 9 H 10 FO 2 Si (M-CH 3 + ) 197.0434, observed 197.0433; LRMS (EI) m / z 197
(M-CH 3 +), 179, 133, 115, 105.
【００５５】 (3) 3-フルオロ-2-トリメチルシリルフェニル イソシアネート (8) 中間体イソシアネートの製造を、クルティウス転移により行った。Capson, T.
L. et al., Tetrahedron Lett., 25, 3515 (1984)及びこれの参考文献を参照の
こと。(2)で製造した化合物 (3.03 g, 14.3 mmol)のCH2Cl2 (20 mL)溶液に、塩 化オキサリル (1.30 mL, 15.0 mmol)を添加し、得られた混合物を室温下で3時間
攪拌した。溶媒の蒸発後に得られた残渣をTHF (10 mL)で希釈し、激しく攪拌し ながらH2O (20 mL) 及びアセトン (50 mL)の氷***液へ注入した。0℃で15分及 び室温で1分後、溶液をEt2O (4 x 50 mL)で抽出し、乾燥 (Na2SO4)した。溶媒の
蒸発後に得られた残渣をトルエン中で1時間30分還流し、溶媒を除去したときに 、2.85 g (79%)のわずかに黄色の油を得た: IR (ニート, cm-1) 2269, 1598, 1
433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) 0.38 (d, J = 1.9 Hz
, 9 H), 6.82 (br t, J = 8.3 Hz, 1 H), 6.90 (br d, J = 8.2 Hz, 1 H), 7.25
(ddd, J1 = J2 = 8.1 Hz, J3 = 6.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) 0.
4, 112.6 (d, JCF = 26 Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF = 2
41 Hz).(3) 3-Fluoro-2-trimethylsilylphenyl isocyanate (8) The intermediate isocyanate was produced by Curtius rearrangement. Capson, T.
See L. et al., Tetrahedron Lett., 25, 3515 (1984) and references thereto. Oxalyl chloride (1.30 mL, 15.0 mmol) was added to a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH 2 Cl 2 (20 mL), and the resulting mixture was allowed to stand at room temperature for 3 hours. Stirred. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and poured into an ice-cold solution of H 2 O (20 mL) and acetone (50 mL) with vigorous stirring. After 15 minutes at 0 ° C. and 1 minute at room temperature, the solution was extracted with Et 2 O (4 × 50 mL) and dried (Na 2 SO 4 ). The residue obtained after evaporation of the solvent was refluxed in toluene for 1 hour 30 minutes to give 2.85 g (79%) of a slightly yellow oil when the solvent was removed: IR (neat, cm -1 ) 2269, 1598, 1
433, 1252, 1228, 846, 788; 1 H NMR (300 MHz, CDCl 3 ) 0.38 (d, J = 1.9 Hz
, 9 H), 6.82 (br t, J = 8.3 Hz, 1 H), 6.90 (br d, J = 8.2 Hz, 1 H), 7.25
(ddd, J 1 = J 2 = 8.1 Hz, J 3 = 6.6 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 0.
4, 112.6 (d, J CF = 26 Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, J CF = 2
41 Hz).
【００５６】 (4) 3-フルオロ-2-トリメチルシリルフェニル イソニトリル (9) 次いで脱酸素化により、予想されるイソニトリルを得た。Baldwin, J. E. et
al., Tetrahedron , 39, 2989 (1983)を参照のこと。トリエチルアミン (4.10 m
L, 29.3 mmol)を、0℃下、2 NトリクロロシランのCH2Cl2 (8.40 mL, 16.8 mmol)
溶液をゆっくりと添加し、5分後、実施例 (3)で製造した化合物 (2.35 g. 11.2
mmol)を添加した。0℃で1時間30分及び室温で30分後、溶液をNH3で飽和し、セラ
イトでろ過し、5% NaH2PO4 で洗浄し、乾燥 (Na2SO4)した。次いで溶媒の蒸発後
に得られた粗生成物をフラッシュクロマトグラフィー (ヘキサン/AcOEt 95:5)に
付し、1.42 g (66%)のわずかに紫色の液体を得た: IR (ニート, cm-1) 2114, 1
598, 1440, 1254, 1237, 1110, 943, 848, 793; 1H NMR (300 MHz, CDCl3) 0.
45 (d, J = 1.8 Hz, 9 H), 7.01 (br t, J = 8.3 Hz, 1 H), 7.17 (br d, J = 7
.7 Hz, 1 H), 7.32 (ddd, J1 = J2 = 8.0 Hz, J3 = 6.1 Hz, 1 H); 13C NMR (7
5 MHz, CDCl3) 0.1, 116.5 (d, JCF = 26 Hz), 124.3, 131.6, 166.8 (d, JCF
= 243 Hz), 166.9; C10H12FNSi (M+) について計算したHRMS (EI) m/z 193.072
3,実測値193.0715; LRMS (EI) m/z 193 (M+), 178, 150, 116, 105.(4) 3-Fluoro-2-trimethylsilylphenyl isonitrile (9) The expected isonitrile was then obtained by deoxygenation. Baldwin, JE et
al., Tetrahedron, 39, 2989 (1983). Triethylamine (4.10 m
L, 29.3 mmol) at 0 ° C under 2 N trichlorosilane in CH 2 Cl 2 (8.40 mL, 16.8 mmol)
The solution was added slowly and after 5 minutes the compound prepared in Example (3) (2.35 g.
mmol) was added. After 1 h 30 at 0 ° C. and 30 min at room temperature, the solution was saturated with NH 3 , filtered through celite, washed with 5% NaH 2 PO 4 and dried (Na 2 SO 4 ). The crude product obtained after evaporation of the solvent was then subjected to flash chromatography (hexane / AcOEt 95: 5) to give 1.42 g (66%) of a slightly purple liquid: IR (neat, cm -1 ) 2114, 1
598, 1440, 1254, 1237, 1110, 943, 848, 793; 1 H NMR (300 MHz, CDCl 3 ) 0.
45 (d, J = 1.8 Hz, 9 H), 7.01 (br t, J = 8.3 Hz, 1 H), 7.17 (br d, J = 7
.7 Hz, 1 H), 7.32 (ddd, J 1 = J 2 = 8.0 Hz, J 3 = 6.1 Hz, 1 H); 13 C NMR (7
5 MHz, CDCl 3 ) 0.1, 116.5 (d, J CF = 26 Hz), 124.3, 131.6, 166.8 (d, J CF
= 243 Hz), 166.9; C 10 H 12 FNSi (M +) for calculated HRMS (EI) m / z 193.072
3, Observed 193.0715; LRMS (EI) m / z 193 (M + ), 178, 150, 116, 105.
【００５７】 (5) (20S)-11-フルオロ-7,12-ビス(トリメチルシリル)カンプトテシン(11) 実施例1-(2) に記載の手順に従い、実施例1-(1)で製造した化合物 (43.5 mg,
0.098 mmol)及び実施例 (4)で製造した化合物 (76 mg, 0.39 mmol)を提供し、フ
ラッシュクロマトグラフィー (CHCl3/アセトン 20:1)後に, 33.4 mg (67%)のわ ずかに黄色の油を得た: []20 D +23.6 (c 0.2, CHCl3) ; 1H NMR (300 MHz, CD
Cl3) 0.53 (d, J = 1.7 Hz, 9 H), 0.60 (s, 9 H), 1.02 (t, J = 7.4 Hz, 3 H
), 1.88 (m, 2 H), 3.82 (br s, 1 H), 5.28 (d, J = 16.3 Hz, 1 H), 5.29 (br
s, 2 H), 5.72 (d, J = 16.3 Hz, 1 H), 7.31 (t, J = 8.7 Hz, 1 H), 7.46 (s
, 1 H), 8.18 (dd, J = 9.2, 5.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3) 1.6,
1.7, 7.7, 31.4, 51.8, 66.3, 72.7, 97.2, 117.8 (d, JCF = 33 Hz), 124.3 (d
, JCF = 28 Hz), 128.9, 131.1, 133.1, 144.4, 146.7, 150.1, 153.4, 157.4,
167.6 (d, JCF = 245 Hz), 173.9; C26H31FN2O4Si2 (M+) について計算したHRM
S (EI) m/z 510.1806,実測値510.1806; LRMS (EI) m/z 510 (M+), 495, 466, 4
51, 395, 319.(5) (20S) -11-fluoro-7,12-bis (trimethylsilyl) camptothecin (11) Compound prepared in Example 1- (1) according to the procedure described in Example 1- (2) (43.5 mg,
0.098 mmol) and the compound prepared in Example (4) (76 mg, 0.39 mmol), after flash chromatography (CHCl 3 / acetone 20: 1), 33.4 mg (67%) slightly yellow Oil obtained: [] 20 D +23.6 (c 0.2, CHCl 3 ); 1 H NMR (300 MHz, CD
Cl 3 ) 0.53 (d, J = 1.7 Hz, 9 H), 0.60 (s, 9 H), 1.02 (t, J = 7.4 Hz, 3 H
), 1.88 (m, 2 H), 3.82 (br s, 1 H), 5.28 (d, J = 16.3 Hz, 1 H), 5.29 (br
s, 2 H), 5.72 (d, J = 16.3 Hz, 1 H), 7.31 (t, J = 8.7 Hz, 1 H), 7.46 (s
, 1 H), 8.18 (dd, J = 9.2, 5.9 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 1.6,
1.7, 7.7, 31.4, 51.8, 66.3, 72.7, 97.2, 117.8 (d, J CF = 33 Hz), 124.3 (d
, J CF = 28 Hz), 128.9, 131.1, 133.1, 144.4, 146.7, 150.1, 153.4, 157.4,
HRM calculated for 167.6 (d, J CF = 245 Hz), 173.9; C 26 H 31 FN 2 O 4 Si 2 (M + )
S (EI) m / z 510.1806, found 510.1806; LRMS (EI) m / z 510 (M + ), 495, 466, 4
51, 395, 319.
【００５８】 (6) (20S)-11-フルオロ-7-トリメチルシリルカンプトテシン (12) 実施例 (5)で製造した化合物(19.5 mg, 0.038 mmol)の48% HBr (1 mL)溶液を5
0℃で20時間加熱した。反応混合物を激しく攪拌しながらゆっくりと飽和NaHCO3
(10 mL)へ注ぎ、AcOEt (6 x 20 mL)で抽出し、乾燥 (Na2SO4)した。溶媒の蒸発 後、残渣をフラッシュクロマトグラフィー (CHCl3/アセトン 8:1)により精製し 、12.5 mg (83%)のわずかに黄色の固体を得た: []20 D +39.6 (c 0.2, CHCl3);
1H NMR (300 MHz, CDCl3) 0.62 (s, 9 H), 1.01 (t, J = 7.4 Hz, 3 H), 1.87
(m, 2 H), 3.81 (br s, 1 H), 5.28 (d, J = 16.4 Hz, 1 H), 5.28 (br s, 2 H
), 5.72 (d, J = 16.4 Hz, 1 H), 7.31 (ddd, J = 9.6, 7.8, 2.8 Hz, 1 H), 7.
61 (s, 1 H), 7.78 (dd, J = 9.7, 2.7 Hz, 1 H), 8.19 (dd, J = 9.4, 5.8 Hz,
1 H); 13C NMR (75 MHz, CDCl3) 1.6, 7.8, 31.5, 51.7, 66.3, 72.7, 97.8,
114.3 (d, JCF = 20 Hz), 117.7 (d, JCF = 26 Hz), 118.5, 128.9, 130.0, 13
3.9, 144.4, 146.1, 149.3, 150.1, 151.7, 157.4, 162.6 (d, JCF = 250 Hz),
173.9; C23H23FN2O4Si (M+) について計算したHRMS (EI) m/z 438.1411,実測値
438.1412; LRMS (EI) m/z 438 (M+), 409, 394, 379, 365, 338, 309. 実施例8 (20S)-10-アミノ-7-トリメチルシリルカンプトテシンの製造(図4参照)(6) (20S) -11-Fluoro-7-trimethylsilylcamptothecin (12) A solution of the compound (19.5 mg, 0.038 mmol) produced in Example (5) in 48% HBr (1 mL) was added to 5
Heat at 0 ° C. for 20 hours. The reaction mixture is stirred vigorously while slowly adding saturated NaHCO 3
(10 mL), extracted with AcOEt (6 × 20 mL) and dried (Na 2 SO 4 ). After evaporation of the solvent, the residue was purified by flash chromatography (CHCl 3 / acetone 8: 1) to give 12.5 mg (83%) of a slightly yellow solid: [] 20 D +39.6 (c 0.2, CHCl 3 3 );
1 H NMR (300 MHz, CDCl 3 ) 0.62 (s, 9 H), 1.01 (t, J = 7.4 Hz, 3 H), 1.87
(m, 2 H), 3.81 (br s, 1 H), 5.28 (d, J = 16.4 Hz, 1 H), 5.28 (br s, 2 H
), 5.72 (d, J = 16.4 Hz, 1 H), 7.31 (ddd, J = 9.6, 7.8, 2.8 Hz, 1 H), 7.
61 (s, 1 H), 7.78 (dd, J = 9.7, 2.7 Hz, 1 H), 8.19 (dd, J = 9.4, 5.8 Hz,
1 H); 13 C NMR (75 MHz, CDCl 3 ) 1.6, 7.8, 31.5, 51.7, 66.3, 72.7, 97.8,
114.3 (d, J CF = 20 Hz), 117.7 (d, J CF = 26 Hz), 118.5, 128.9, 130.0, 13
3.9, 144.4, 146.1, 149.3, 150.1, 151.7, 157.4, 162.6 (d, J CF = 250 Hz),
173.9; C 23 H 23 FN 2 O 4 Si (M +) for calculated HRMS (EI) m / z 438.1411 , Found
438.1412; LRMS (EI) m / z 438 (M + ), 409, 394, 379, 365, 338, 309.Example 8 Production of (20S) -10-amino-7-trimethylsilylcamptothecin (see FIG. 4)
【００５９】 [0059]
【００６０】 (1) 4-tert-ブチルオキシカルボニルアミノフェニル イソニトリル (18) イソニトリルを、古典的Boc-保護、続く脱水による2工程により製造した。Ein
horn, J. et al., Synlett, 37 (1991)を参照のこと。4-アミノホルムアミド (1
.71 g, 12.6 mmol)、ジ-tert-ブチルジカーボネート(2.87 g, 13.2 mmol)及びNa
HCO3 (1.11 g, 13.2 mmol)の無水EtOH (50 mL)中の混合物を、洗浄浴中4時間超 音波処理した。最終の溶液をセライトのパッドでろ過し、乾燥物まで濃縮した。
残渣を半塩水(50 mL)中に集め、AcOEt (6 x 30 mL)で抽出し、乾燥(Na2SO4)した
。溶媒の蒸発後、残った油をフラッシュクロマトグラフィー (CHCl3/MeOH 95:5)
に付し、2.85 g (96%)の4-tert-ブチルオキシカルボニルアミノホルムアミドを 白色固体として得た。この中間体(945 mg, 4.0 mmol)を実施例5-(1)に記載の条 件に付し、フラッシュクロマトグラフィー (ヘキサン/AcOEt 9:1)後に、502 mg
(58%)のわずかに褐色の固体を得た: IR (NaCl, cm-1) 3370, 2121, 1691, 1524
, 1412, 1364, 1239, 1158, 832; 1H NMR (300 MHz, CDCl3) 1.48 (s, 9 H),
6.75 (br s, 1 H), 7.26 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2 H);
13C NMR (75 MHz, CDCl3) 28.2, 81.3, 118.5, 127.1, 139.4, 152.3, 162.7;
C12H14N2O2 (M+) について計算したHRMS (EI) m/z 218.1055,実測値218.1044;
LRMS (EI) m/z 218 (M+), 162, 144.(1) 4-tert-butyloxycarbonylaminophenyl isonitrile (18) isonitrile was prepared by two steps with classical Boc-protection followed by dehydration. Ein
See horn, J. et al., Synlett, 37 (1991). 4-aminoformamide (1
.71 g, 12.6 mmol), di-tert-butyl dicarbonate (2.87 g, 13.2 mmol) and Na
A mixture of HCO 3 (1.11 g, 13.2 mmol) in anhydrous EtOH (50 mL) was sonicated in a washing bath for 4 hours. The final solution was filtered through a pad of celite and concentrated to dryness.
The residue was collected in brackish water (50 mL), extracted with AcOEt (6 × 30 mL) and dried (Na 2 SO 4 ). After evaporation of the solvent, the remaining oil was flash chromatographed (CHCl 3 / MeOH 95: 5)
To give 2.85 g (96%) of 4-tert-butyloxycarbonylaminoformamide as a white solid. This intermediate (945 mg, 4.0 mmol) was subjected to the conditions described in Example 5- (1) and, after flash chromatography (hexane / AcOEt 9: 1), 502 mg
(58%) slightly brown solid was obtained: IR (NaCl, cm −1 ) 3370, 2121, 1691, 1524
, 1412, 1364, 1239, 1158, 832; 1 H NMR (300 MHz, CDCl 3 ) 1.48 (s, 9 H),
6.75 (br s, 1 H), 7.26 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2 H);
13 C NMR (75 MHz, CDCl 3 ) 28.2, 81.3, 118.5, 127.1, 139.4, 152.3, 162.7;
C 12 H 14 N 2 O 2 (M +) for calculated HRMS (EI) m / z 218.1055 , Found 218.1044;
LRMS (EI) m / z 218 (M + ), 162, 144.
【００６１】 (2)(20S)-10-tert-ブチルオキシカルボニルアミノ-7-トリメチルシリル カンプ トテシン (19) 実施例1-(2)に記載の手順に従い、実施例1-(1)で製造した化合物(44.5 mg, 0.
10 mmol)及び実施例 (1)で製造した化合物(65 mg, 0.30 mmol)を供給し、フラッ
シュクロマトグラフィー (CHCl3/アセトン 6:1)の後に、32.5 mg (60%)のわずか
に黄色の固体を得た: []20 D +28.0 (c 0.2, CHCl3); 1H NMR (300 MHz, CDCl3 ) 0.63 (s, 9 H), 0.99 (t, J = 7.4 Hz, 3 H), 1.53 (s, 9 H), 1.86 (m, 2
H), 4.03 (br s, 1 H), 5.24 (d, J = 16.2 Hz, 1 H), 5.26 (s, 2 H), 5.70 (d
, J = 16.2 Hz, 1 H), 7.00 (br s, 1 H), 7.47 (dd, J = 9.2, 2.3 Hz, 1 H),
7.55 (s, 1 H), 8.02 (d, J = 9.2 Hz, 1 H), 8.56 (br s, 1 H); 13C NMR (75
MHz, CDCl3) 1.3, 7.8, 28.2, 31.5, 51.8, 66.3, 72.8, 97.1, 114.4, 117.8
, 122.6, 131.3, 132.8, 135.0, 137.2, 142.9, 144.3, 146.6, 149.2, 150.1,
157.4, 173.9; C23H25N3O4Si (M-Boc+) について計算したHRMS (EI) m/z 435.1
614,実測値435.1612; LRMS (EI) m/z 535 (M+), 479, 435, 391, 362, 335.(2) (20S) -10-tert-butyloxycarbonylamino-7-trimethylsilyl camptothecin (19) Prepared in Example 1- (1) according to the procedure described in Example 1- (2) Compound (44.5 mg, 0.
10 mmol) and the compound prepared in Example (1) (65 mg, 0.30 mmol) were fed and, after flash chromatography (CHCl 3 / acetone 6: 1), 32.5 mg (60%) of slightly yellow A solid was obtained: [] 20 D +28.0 (c 0.2, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) 0.63 (s, 9 H), 0.99 (t, J = 7.4 Hz, 3 H), 1.53 (s, 9 H), 1.86 (m, 2
H), 4.03 (br s, 1 H), 5.24 (d, J = 16.2 Hz, 1 H), 5.26 (s, 2 H), 5.70 (d
, J = 16.2 Hz, 1 H), 7.00 (br s, 1 H), 7.47 (dd, J = 9.2, 2.3 Hz, 1 H),
7.55 (s, 1 H), 8.02 (d, J = 9.2 Hz, 1 H), 8.56 (br s, 1 H); 13 C NMR (75
MHz, CDCl 3 ) 1.3, 7.8, 28.2, 31.5, 51.8, 66.3, 72.8, 97.1, 114.4, 117.8
, 122.6, 131.3, 132.8, 135.0, 137.2, 142.9, 144.3, 146.6, 149.2, 150.1,
157.4, 173.9; C 23 H 25 N 3 O 4 Si (M-Boc +) HRMS calculated for (EI) m / z 435.1
614, found 435.1612; LRMS (EI) m / z 535 (M + ), 479, 435, 391, 362, 335.
【００６２】 (3) (20S)-10-アミノ-7-トリメチルシリルカンプトテシン (20) 実施例 (2)で製造した化合物 (75.5 mg, 0.141 mmol)及びTFA (500 mL)のCH2C
l2 (2 mL)溶液を、室温下で3時間攪拌した。次いで反応混合物を飽和NaHCO3 (50
mL)へ注ぎ、AcOEt (10 x 15 mL)で抽出し、乾燥(Na2SO4)した。溶媒を蒸発させ
た後に得られた残渣を、フラッシュクロマトグラフィー (CHCl3/MeOH 95:5)によ
り精製し、55.4 mg (90%)の黄色の固体を得た: []20 D +18.7 (c 0.15, CHCl3/M
eOH 4:1); 1H NMR (300 MHz, CDCl3/CD3OD 4:1) 0.40 (s, 9 H), 0.80 (t, J
= 7.4 Hz, 3 H), 1.70 (m, 2 H), 5.05 (s, 2 H), 5.08 (d, J = 16.3 Hz, 1 H
), 5.43 (d, J = 16.3 Hz, 1 H), 7.05 (br s, 1 H), 7.07 (d, J = 8.0 Hz, 1
H), 7.38 (s, 1 H), 7.74 (d, J = 8.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3/CD 3 OD 4:1) 0.6, 7.2, 30.8, 51.8, 65.5, 72.7, 97.0, 107.2, 116.8, 122.0, 1
30.7, 134.0, 134.7, 139.9, 141.7, 145.8, 146.9, 151.2, 157.5, 173.7; C2 3 H25N3O4Si (M+) について計算したHRMS (EI) m/z 435.1614,実測値435.1613;
LRMS (EI) m/z 435 (M+), 391, 376, 335, 290. 実施例9 (20S)-11-アミノ-7-トリメチルシリルカンプトテシンの製造(3) (20S) -10-Amino-7-trimethylsilylcamptothecin (20) CH of the compound (75.5 mg, 0.141 mmol) produced in Example (2) and TFA (500 mL)TwoC
lTwo (2 mL) solution was stirred at room temperature for 3 hours. The reaction mixture was then washed with saturated NaHCOThree (50
mL), extracted with AcOEt (10 x 15 mL), dried (NaTwoSOFour)did. Evaporate the solvent
The residue obtained after flash chromatography (CHClThree/ MeOH 95: 5)
Purification yielded 55.4 mg (90%) of a yellow solid: []20 D +18.7 (c 0.15, CHClThree/ M
eOH 4: 1);1H NMR (300 MHz, CDClThree/ CDThreeOD 4: 1) 0.40 (s, 9 H), 0.80 (t, J
= 7.4 Hz, 3 H), 1.70 (m, 2 H), 5.05 (s, 2 H), 5.08 (d, J = 16.3 Hz, 1 H
), 5.43 (d, J = 16.3 Hz, 1 H), 7.05 (br s, 1 H), 7.07 (d, J = 8.0 Hz, 1
H), 7.38 (s, 1 H), 7.74 (d, J = 8.0 Hz, 1 H);13C NMR (75 MHz, CDClThree/ CD Three OD 4: 1) 0.6, 7.2, 30.8, 51.8, 65.5, 72.7, 97.0, 107.2, 116.8, 122.0, 1
30.7, 134.0, 134.7, 139.9, 141.7, 145.8, 146.9, 151.2, 157.5, 173.7; CTwo Three Htwenty fiveNThreeOFourSi (M+HRMS (EI) m / z 435.1614, found 435.1613;
LRMS (EI) m / z 435 (M+), 391, 376, 335, 290. Example 9 Production of (20S) -11-amino-7-trimethylsilylcamptothecin
【００６３】 [0063]
【００６４】 (1) 3-tert-ブチルオキシカルボニルアミノフェニル イソニトリル イソニトリルを、実施例9-(1)記載の手順と同一の手順に従い2工程で製造した
。第一工程においては、3-アミノホルムアミド (1.80 g, 13.2 mmol)のBoc-保護
を提供し、フラッシュクロマトグラフィー (CHCl3/MeOH 95:5)後、2.65 g (85%)
の3-tert-ブチルオキシカルボニルアミノホルムアミドを白色固体として得た。 次いでこの中間体(412 mg, 1.74 mmol)を実施例5-(1)に記載の条件に付し、フラ
ッシュクロマトグラフィー (ヘキサン/AcOEt 9:1)後、190 mg (50%)の褐色の固 体を得た: IR (NaCl, cm-1) 3318, 2126, 1715, 1603, 1547, 1433, 1236, 116
2, 782; 1H NMR (300 MHz, CDCl3) 1.49 (s, 9 H), 6.67 (br s, 1 H), 7.00
(m, 1 H), 7.20-7.30 (m, 2 H), 7.60 (br s, 1 H); 13C NMR (75 MHz, CDCl3)
28.2, 81.3, 116.0, 118.9, 120.6, 129.8, 139.5, 152.3, 163.6; C12H14N2 O2 (M+) について計算したHRMS (EI) m/z 218.1055,実測値218.1047; LRMS (EI
) m/z 218 (M+), 196, 162, 152, 118.(1) 3-tert-butyloxycarbonylaminophenyl isonitrile Isonitrile was prepared in two steps according to the same procedure as described in Example 9- (1). In the first step, to provide 3-amino-formamide (1.80 g, 13.2 mmol) and Boc- protection, flash chromatography (CHCl 3 / MeOH 95: 5 ) after, 2.65 g (85%)
Of 3-tert-butyloxycarbonylaminoformamide was obtained as a white solid. Then, this intermediate (412 mg, 1.74 mmol) was subjected to the conditions described in Example 5- (1), and after flash chromatography (hexane / AcOEt 9: 1), 190 mg (50%) of a brown solid was obtained. Obtained body: IR (NaCl, cm -1 ) 3318, 2126, 1715, 1603, 1547, 1433, 1236, 116
2, 782; 1 H NMR (300 MHz, CDCl 3 ) 1.49 (s, 9 H), 6.67 (br s, 1 H), 7.00
(m, 1 H), 7.20-7.30 (m, 2 H), 7.60 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 )
28.2, 81.3, 116.0, 118.9, 120.6, 129.8, 139.5, 152.3, 163.6; HRMS (EI) m / z 218.1055 calculated for C 12 H 14 N 2 O 2 (M + ), found 218.1047; LRMS (EI
) m / z 218 (M + ), 196, 162, 152, 118.
【００６５】 (2) (20S)-11-アミノ-7-トリメチルシリルカンプトテシン 実施例1-(2) に記載の手順に従い、実施例1-(1)で製造した化合物 (44.5 mg,
0.10 mmol)及び実施例 (1)で製造した化合物(65.5 mg, 0.3 mmol)を得、フラッ シュクロマトグラフィー (CHCl3/MeOH 95:5; CHCl3/アセトン 5:1)の後、23.1 m
g (43%)のわずかに黄色の油を得た。この中間体(14.7 mg, 0.027 mmol)を、実施
例9-(3)に記載の条件に従い脱保護し、フラッシュクロマトグラフィー (CHCl3/M
eOH 9:1)の後、その他の異性体を除いて、11.8 mg (99%)の(20S)-11-アミノ-7- トリメチルシリルカンプトテシンを黄色の固体として得た: []20 D +15.0 (c 0.
1, CHCl3/MeOH 4:1); 1H NMR (300 MHz, CDCl3/CD3OD 4:1) 0.44 (s, 9 H), 0
.86 (t, J = 7.4 Hz, 3 H), 1.76 (m, 2 H), 5.08 (s, 2 H), 5.14 (d, J = 16
.4 Hz, 1 H), 5.50 (d, J = 16.3 Hz, 1 H), 6.97 (dd, J = 9.2, 2.5 Hz, 1 H)
, 7.07 (d, J = 2.5 Hz, 1 H), 7.50 (s, 1 H), 7.84 (d, J = 9.2 Hz, 1 H); 13 C NMR (75 MHz, CDCl3/CD3OD 4:1) 1.1, 7.4, 31.0, 51.7, 65.6, 97.9, 107
.9, 117.8, 119.7, 125.9, 127.1, 129.0, 130.4, 135.4, 144.3, 149.5, 149.9
, 151.1, 157.6, 175.3; C23H25N3O4Si (M+) について計算したHRMS (EI) m/z
435.1614,実測値435.1626; LRMS (EI) m/z 435 (M+), 406, 391, 376, 335. 実施例10 (20S)-11-フルオロ-10-アミノ-7-トリメチルシリルカンプトテシンの製造(図5 参照)(2) (20S) -11-Amino-7-trimethylsilylcamptothecin The compound prepared in Example 1- (1) according to the procedure described in Example 1- (2) (44.5 mg,
0.10 mmol) and the compound prepared in Example (1) (65.5 mg, 0.3 mmol) were obtained by flash chromatography (CHClThree/ MeOH 95: 5; CHClThree/ Acetone 5: 1), then 23.1 m
g (43%) of a slightly yellow oil was obtained. This intermediate (14.7 mg, 0.027 mmol) was
Deprotection was performed according to the conditions described in Example 9- (3), followed by flash chromatography (CHClThree/ M
After eOH 9: 1), excluding the other isomers, 11.8 mg (99%) of (20S) -11-amino-7-trimethylsilylcamptothecin was obtained as a yellow solid: []20 D +15.0 (c 0.
1, CHClThree/ MeOH 4: 1);1H NMR (300 MHz, CDClThree/ CDThreeOD 4: 1) 0.44 (s, 9 H), 0
.86 (t, J = 7.4 Hz, 3 H), 1.76 (m, 2 H), 5.08 (s, 2 H), 5.14 (d, J = 16
.4 Hz, 1 H), 5.50 (d, J = 16.3 Hz, 1 H), 6.97 (dd, J = 9.2, 2.5 Hz, 1 H)
, 7.07 (d, J = 2.5 Hz, 1 H), 7.50 (s, 1 H), 7.84 (d, J = 9.2 Hz, 1 H); 13 C NMR (75 MHz, CDClThree/ CDThree(OD 4: 1) 1.1, 7.4, 31.0, 51.7, 65.6, 97.9, 107
.9, 117.8, 119.7, 125.9, 127.1, 129.0, 130.4, 135.4, 144.3, 149.5, 149.9
, 151.1, 157.6, 175.3; Ctwenty threeHtwenty fiveNThreeOFourSi (M+HRMS (EI) m / z calculated for)
435.1614, observed 435.1626; LRMS (EI) m / z 435 (M+), 406, 391, 376, 335.Example 10 Production of (20S) -11-fluoro-10-amino-7-trimethylsilylcamptothecin (see FIG. 5)
【００６６】 [0066]
【００６７】 (1) 4-tert-ブチルオキシカルボニルアミノ-3-フルオロ-1-ニトロベンゼン(22) 2-フルオロ-4-ニトロアニリン(21) [Katritsky, A. R. et al., J. Org. Chem
., 51, 5039 (1986)に従い製造] (2.16 g, 13.9 mmol)のCH2Cl2 (25 mL)溶液に 、ジ-tert-ブチルジカーボネート(3.19 g, 14.6 mmol)、トリエチルアミン (2.9
5 mL, 20.8 mmol)及び4-ジメチルアミノピリジン (210 mg, 1.67 mmol)を連続的
に添加し、反応混合物を室温下で16時間攪拌した。最終の溶液をCH2Cl2 (75 mL)
で希釈し、氷冷5% クエン酸 (4 x 50 mL)で洗浄し、乾燥(Na2SO4)した。溶媒を 除去後、残渣をフラッシュクロマトグラフィー (ヘキサン/AcOEt 9:5)に付し、 溶離順に最初に1.95 g (55%)のモノ−保護誘導体である4-tert-ブチルオキシカ ルボニルアミノ-3-フルオロ-1-ニトロベンゼンを、第二に1.13 g (23%)のビス−
保護誘導体である4-ジ-tert-ブチルオキシカルボニルアミノ-3-フルオロ-1-ニト
ロベンゼンを得た。モノ−保護誘導体の特徴は以下の通りであった: 1H NMR (3
00 MHz, CDCl3) 1.52 (s, 9 H), 6.99 (br s, 1 H), 7.95 (m, 1 H), 8.03 (br
d, J = 9.2 Hz, 1 H), 8.34 (br t, J = 8.5 Hz, 1 H); 13C NMR (75 MHz, CD
Cl3) 28.1, 82.5, 110.9 (d, JCF = 23 Hz), 118.3, 120.8, 133.5, 141.7, 15
0.1 (d, JCF = 243 Hz), 151.4; C11H13FN2O4 (M+) について計算したHRMS (EI
) m/z 256.0859,実測値258.0854; LRMS (EI) m/z 256 (M+), 200, 182, 57.(1) 4-tert-butyloxycarbonylamino-3-fluoro-1-nitrobenzene (22) 2-fluoro-4-nitroaniline (21) [Katritsky, AR et al., J. Org. Chem.
, 51, 5039 (1986)] (2.16 g, 13.9 mmol) in CH 2 Cl 2 (25 mL), di-tert-butyl dicarbonate (3.19 g, 14.6 mmol), triethylamine (2.9
5 mL, 20.8 mmol) and 4-dimethylaminopyridine (210 mg, 1.67 mmol) were added successively, and the reaction mixture was stirred at room temperature for 16 hours. Final solution was CH 2 Cl 2 (75 mL)
And washed with ice-cold 5% citric acid (4 × 50 mL) and dried (Na 2 SO 4 ). After removal of the solvent, the residue was subjected to flash chromatography (hexane / AcOEt 9: 5), eluting first with 1.95 g (55%) of the mono-protected derivative 4-tert-butyloxycarbonylamino-3-fluoro 1-Nitrobenzene was secondly converted to 1.13 g (23%) of bis-
The protected derivative 4-di-tert-butyloxycarbonylamino-3-fluoro-1-nitrobenzene was obtained. The characteristics of the mono-protected derivative were as follows: 1 H NMR (3
00 MHz, CDCl 3 ) 1.52 (s, 9 H), 6.99 (br s, 1 H), 7.95 (m, 1 H), 8.03 (br
d, J = 9.2 Hz, 1 H), 8.34 (br t, J = 8.5 Hz, 1 H); 13 C NMR (75 MHz, CD
Cl 3 ) 28.1, 82.5, 110.9 (d, J CF = 23 Hz), 118.3, 120.8, 133.5, 141.7, 15
HRMS (EI) calculated for 0.1 (d, J CF = 243 Hz), 151.4; C 11 H 13 FN 2 O 4 (M + )
) m / z 256.0859, found 258.0854; LRMS (EI) m / z 256 (M + ), 200, 182, 57.
【００６８】 (2) 4-tert-ブチルオキシカルボニルアミノ-3-フルオロアニリン (24) ニトロ基のアミン基への還元を、古典的手順に従い行った。Ram, S. et al.,
Tetrahedron Lett., 25, 3415 (1984)を参照のこと。実施例 (1)で製造した化合
物 (1.62 g, 6.32 mmol)及びギ酸アンモニウム(1.70 g, 27 mmol)の無水MeOH (1
2 mL)溶液に、10% Pd-C (400 mg)を一度に添加した。室温で2時間後、最終の溶 液をセライトでろ過し、濃縮し、残渣を直接フラッシュクロマトグラフィー (CH
Cl3/MeOH 9:1)に付し、1.40 g (98%)のわずかに黄色の油を得た: 1H NMR (300
MHz, CD3SOCD3) 1.40 (s, 9 H), 5.22 (s, 2 H), 6.25-6.35 (m, 2 H), 6.93 (
br t, J = 8.0 Hz, 1 H), 8.29 (br s, 1 H); 13C NMR (75 MHz, CDCl3) 28.5
, 80.4, 102.1 (d, JCF = 24 Hz), 110.7, 117.2, 122.8, 143.4, 153.1, 154.1
(d, JCF = 244 Hz); C11H15FN2O2 (M+) について計算したHRMS (EI) m/z 226.
1118,実測値226.1116; LRMS (EI) m/z 226 (M+), 170, 126, 83, 57.(2) 4-tert-butyloxycarbonylamino-3-fluoroaniline (24) Reduction of the nitro group to the amine group was performed according to classical procedures. Ram, S. et al.,
See Tetrahedron Lett., 25, 3415 (1984). Compound (1.62 g, 6.32 mmol) produced in Example (1) and ammonium formate (1.70 g, 27 mmol) in anhydrous MeOH (1
To 2 mL) solution was added 10% Pd-C (400 mg) in one portion. After 2 hours at room temperature, the final solution was filtered through celite, concentrated and the residue was directly flash chromatographed (CH
Cl 3 / MeOH 9: 1) to give 1.40 g (98%) of a slightly yellow oil: 1 H NMR (300
MHz, CD 3 SOCD 3 ) 1.40 (s, 9 H), 5.22 (s, 2 H), 6.25-6.35 (m, 2 H), 6.93 (
br t, J = 8.0 Hz, 1 H), 8.29 (br s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 28.5
, 80.4, 102.1 (d, J CF = 24 Hz), 110.7, 117.2, 122.8, 143.4, 153.1, 154.1
(d, J CF = 244 Hz ); C 11 H 15 FN 2 O 2 (M +) HRMS calculated for (EI) m / z 226.
1118, found 226.1116; LRMS (EI) m / z 226 (M + ), 170, 126, 83, 57.
【００６９】 (3) 4-tert-ブチルオキシカルボニルアミノ-3-フルオロフェニル イソニトリル(
25) ジシクロヘキシルカルボジイミド (1.51 g, 7.31 mmol)のCH2Cl2 (15 mL)攪拌
溶液に、0℃下、ギ酸 (275 mL, 7.31 mmol)を滴下した。10 分後、得られた混合
物を、CH2Cl2 (10 mL)及びピリジン (0.61 mL, 7.50 mmol)中の実施例 (2)で製 造した化合物 (1.28 g, 5.66 mmol)の溶液へ5分かけて添加した。次いで反応混 合物を室温まで暖め、16時間攪拌した。セライトでろ過した後、最終の溶液を濃
縮し、フラッシュクロマトグラフィー (CHCl3/AcOEt 85:15)に付し、1.44 g (10
0%)の4-tert-ブチルオキシカルボニルアミノ-3-フルオロホルムアミドを白色固 体として得た。この中間体(1.38 g, 5.43 mmol)をCH2Cl2 (20 mL)に0℃下で溶解
し、テトラブロモメタン (1.93 g, 5.80 mmol)、トリフェニルホスフィン (1.52
g, 5.80 mmol)及び1.4-ジアザビシクロ[2.2.2]オクタン (DABCO, 650 mg, 5.80
mmol)を連続的に添加した。反応混合物を室温まで暖め、2時間攪拌した。溶媒 を蒸発させた後、粗生成物を氷冷Et2O (20 mL)で摩砕し、セライトでろ過した。
溶媒の蒸発後に得られた残渣をフラッシュクロマトグラフィー (ヘキサン/AcOEt
95:5〜9:1)により精製し、660 mg (51%)のわずかに褐色の固体を得た: 1H NMR
(300 MHz, CDCl3) 1.51 (s, 9 H), 6.76 (br s, 1 H), 7.05-7.20 (m, 2 H),
8.17 (br t, J = 8.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) 28.1, 81.8, 113.
3 (d, JCF = 25 Hz), 119.7, 123.0, 128.6, 150.6 (d, JCF = 242 Hz), 151.8,
164.2; C12H13FN2O2 (M+) について計算したHRMS (EI) m/z 236.0961,実測値2
36.0952; LRMS (EI) m/z 236 (M+), 180, 163, 136, 08, 57.(3) 4-tert-butyloxycarbonylamino-3-fluorophenyl isonitrile (
25) Formic acid (275 mL, 7.31 mmol) was added dropwise to a stirred solution of dicyclohexylcarbodiimide (1.51 g, 7.31 mmol) in CH 2 Cl 2 (15 mL) at 0 ° C. After 10 minutes, the resulting mixture was added to a solution of the compound prepared in Example (2) (1.28 g, 5.66 mmol) in CH 2 Cl 2 (10 mL) and pyridine (0.61 mL, 7.50 mmol). Added over minutes. The reaction mixture was then warmed to room temperature and stirred for 16 hours. After filtration through celite, the final solution was concentrated and subjected to flash chromatography (CHCl 3 / AcOEt 85:15) to give 1.44 g (10
0%) of 4-tert-butyloxycarbonylamino-3-fluoroformamide as a white solid. This intermediate (1.38 g, 5.43 mmol) was dissolved in CH 2 Cl 2 (20 mL) at 0 ° C., tetrabromomethane (1.93 g, 5.80 mmol), triphenylphosphine (1.52
g, 5.80 mmol) and 1.4-diazabicyclo [2.2.2] octane (DABCO, 650 mg, 5.80
mmol) were added continuously. The reaction mixture was warmed to room temperature and stirred for 2 hours. After evaporation of the solvent, the crude product was triturated with ice-cold Et 2 O (20 mL) and filtered through celite.
The residue obtained after evaporation of the solvent is subjected to flash chromatography (hexane / AcOEt
95: 5-9: 1) to give 660 mg (51%) of a slightly brown solid: 1 H NMR
(300 MHz, CDCl 3 ) 1.51 (s, 9 H), 6.76 (br s, 1 H), 7.05-7.20 (m, 2 H),
8.17 (br t, J = 8.6 Hz, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 28.1, 81.8, 113.
3 (d, J CF = 25 Hz), 119.7, 123.0, 128.6, 150.6 (d, J CF = 242 Hz), 151.8,
164.2; C 12 H 13 FN 2 O 2 (M +) HRMS calculated for (EI) m / z 236.0961, Found 2
36.0952; LRMS (EI) m / z 236 (M + ), 180, 163, 136, 08, 57.
【００７０】 (4) (20S)-10-tert-ブチルオキシカルボニルアミノ-11-フルオロ-7-トリメチル シリル-カンプトテシン(26)及び(20S)-10-tert-ブチルオキシカルボニルアミノ-
9-フルオロ-7-トリメチルシリルカンプトテシン(27) (それぞれが1.9:1の混合物
)(4) (20S) -10-tert-butyloxycarbonylamino-11-fluoro-7-trimethylsilyl-camptothecin (26) and (20S) -10-tert-butyloxycarbonylamino-
9-fluoro-7-trimethylsilylcamptothecin (27) (1.9: 1 mixture each
)
【００７１】 [0071]
【００７２】 実施例1-(2)に記載の手順に従い、実施例1-(1)で製造した化合物(66.8 mg, 0.
15 mmol)及び実施例 (3)で製造した化合物(110 mg, 0.50 mmol)を提供し、フラ ッシュクロマトグラフィー (CHCl3/MeOH 96:4; CHCl3/アセトン 10:1)の後、前 記位置異性体を含む47.6 mg (57%)のわずかに黄色の油を得た: 1H NMR (300 MH
z, CDCl3) 0.54 (d, J = 4.9 Hz, 9 Hマイナー), 0.65 (s, 9 Hメシ゛ャー), 0.99 (t, J = 7.3 Hz, 3 H), 1.86 (m, 2 H), 3.93 (br s, 1 H), 5.24 (d, J = 16.3 Hz,
1 Hマイナー), 5.25 (br s, 2 Hメシ゛ャー), 5.25 (d, J = 16.3 Hz, 1 Hメシ゛ャー), 5.30 (
br s, 2 Hマイナー), 5.68 (d, J = 16.3 Hz, 1 Hマイナー), 5.69 (d, J = 16.3 Hz, 1
Hメシ゛ャー), 6.98 (d, J = 3.6 Hz, 1 Hマイナー), 7.02 (d, J = 3.6 Hz, 1 Hメシ゛ャー),
7.52 (s, 1 Hマイナー), 7.53 (s, 1 Hメシ゛ャー), 7.74 (d, J = 12.1 Hz, 1 Hメシ゛ャー),
7.92 (br d, J = 9.3 Hz, 1 Hマイナー), 8.60 (br t, J = 8.4 Hz, 1 Hマイナー), 9.08
(d, J = 8.7 Hz, 1 Hメシ゛ャー); C28H32FN3O6Siについて計算したHRMS (EI) m/z 553.2044,実測値553.2022; LRMS (EI) m/z 553 (M+), 493, 479, 453, 435, 42
4, 409, 394, 380, 353.According to the procedure described in Example 1- (2), the compound prepared in Example 1- (1) (66.8 mg, 0.2%
15 mmol) and the compound prepared in Example (3) (110 mg, 0.50 mmol) were provided, and after flash chromatography (CHCl 3 / MeOH 96: 4; CHCl 3 / acetone 10: 1), Obtained 47.6 mg (57%) of a slightly yellow oil containing the regioisomer: 1 H NMR (300 MH
z, CDCl 3 ) 0.54 (d, J = 4.9 Hz, 9 H minor ), 0.65 (s, 9 H mesher ), 0.99 (t, J = 7.3 Hz, 3 H), 1.86 (m, 2 H), 3.93 (br s, 1 H), 5.24 (d, J = 16.3 Hz,
1H minor ), 5.25 (br s, 2H mesher ), 5.25 (d, J = 16.3 Hz, 1H mesher ), 5.30 (
br s, 2 H minor ), 5.68 (d, J = 16.3 Hz, 1 H minor ), 5.69 (d, J = 16.3 Hz, 1
H measure ), 6.98 (d, J = 3.6 Hz, 1 H minor ), 7.02 (d, J = 3.6 Hz, 1 H measure ),
7.52 (s, 1 H minor ), 7.53 (s, 1 H mesher ), 7.74 (d, J = 12.1 Hz, 1 H mesher ),
7.92 (br d, J = 9.3 Hz, 1 H minor ), 8.60 (br t, J = 8.4 Hz, 1 H minor ), 9.08
(d, J = 8.7 Hz, 1 H joint catcher over); C 28 H 32 FN 3 O 6 Si HRMS calculated for (EI) m / z 553.2044, Found 553.2022; LRMS (EI) m / z 553 (M +) , 493, 479, 453, 435, 42
4, 409, 394, 380, 353.
【００７３】 (5) (20S)-10-アミノ-11-フルオロ-7-トリメチルシリルカンプトテシン(28) 実施例 (4)で製造した化合物 (41.3 mg, 0.0746 mmol)を、実施例9-(3)に記載
の条件に従い脱保護した。ワークアップ（workup）後、粗生成物をフラッシュク
ロマトグラフィー (CHCl3/アセトン/MeOH 70:10:1.5)に付し、溶離順に最初に14
.1 mg (42%)の純粋な(20S)-10-アミノ-11-フルオロ-7-トリメチルシリル-カンプ
トテシン、次いで (20S)-10-アミノ-11-フルオロ-7-トリメチルシリルカンプト テシン及び(20S)-10-アミノ-9-フルオロ-7-トリメチルシリルカンプトテシンの 約1:1混合物15.2 mgを得た。(20S)-10-アミノ-11-フルオロ-7-トリメチルシリル
カンプトテシンの特徴は以下の通りであった: []20 D +20.0 (c 0.2, CHCl3/MeO
H 4:1); 1H NMR (300 MHz, CDCl3) 0.59 (s, 9 H), 1.00 (t, J = 7.4 Hz, 3
H), 1.86 (m, 2 H), 3.86 (br s, 1 H), 4.31 (br s, 2 H), 5.21 (br s, 2 H),
5.26 (d, J = 16.4 Hz, 1 H), 5.69 (d, J = 16.4 Hz, 1 H), 7.30 (d, J = 9.
3 Hz, 1 H), 7.50 (s, 1 H), 7.69 (d, J = 11.8 Hz, 1 H); 13C NMR (75 MHz,
CDCl3/CD3OD 10:1) 1.4, 7.7, 31.4, 51.9, 66.1, 72.7, 97.1, 109.4, 113.6
(d, JCF = 20 Hz), 117.3, 130.8, 134.4, 136.4, 140.2, 142., 146.5, 147.6,
150.6, 153.9, 154.0 (d, JCF = 251 Hz), 157.6, 173.9; C23H24FN3O4Si (M+ ) について計算したHRMS (EI) m/z 453.1520,実測値453.1500; LRMS (EI) m/z
453 (M+), 424, 409, 394, 352, 181, 131, 119. 実施例11 (20S)-11,12-ジフルオロ7-トリメチルシリルカンプトテシン及び(20S)-9,10-ジ フルオロ7-トリメチルシリルカンプトテシン(それぞれ3:1の混合物)の製造(5) (20S) -10-Amino-11-fluoro-7-trimethylsilylcamptothecin (28) The compound (41.3 mg, 0.0746 mmol) produced in Example (4) was treated in Example 9- (3) Deprotection was performed according to the conditions described in. After workup, the crude product was subjected to flash chromatography (CHCl 3 / acetone / MeOH 70: 10: 1.5), eluting first with 14
.1 mg (42%) of pure (20S) -10-amino-11-fluoro-7-trimethylsilyl-camptothecin, followed by (20S) -10-amino-11-fluoro-7-trimethylsilylcamptothecin and (20S) 15.2 mg of an approximately 1: 1 mixture of -10-amino-9-fluoro-7-trimethylsilylcamptothecin was obtained. The characteristics of (20S) -10-amino-11-fluoro-7-trimethylsilylcamptothecin were as follows: [] 20 D +20.0 (c 0.2, CHCl 3 / MeO
H 4: 1); 1 H NMR (300 MHz, CDCl 3 ) 0.59 (s, 9 H), 1.00 (t, J = 7.4 Hz, 3
H), 1.86 (m, 2 H), 3.86 (br s, 1 H), 4.31 (br s, 2 H), 5.21 (br s, 2 H),
5.26 (d, J = 16.4 Hz, 1 H), 5.69 (d, J = 16.4 Hz, 1 H), 7.30 (d, J = 9.
3 Hz, 1 H), 7.50 (s, 1 H), 7.69 (d, J = 11.8 Hz, 1 H); 13 C NMR (75 MHz,
(CDCl 3 / CD 3 OD 10: 1) 1.4, 7.7, 31.4, 51.9, 66.1, 72.7, 97.1, 109.4, 113.6
(d, J CF = 20 Hz), 117.3, 130.8, 134.4, 136.4, 140.2, 142., 146.5, 147.6,
150.6, 153.9, 154.0 (d, J CF = 251 Hz), 157.6, 173.9; HRMS (EI) m / z 453.1520 calculated for C 23 H 24 FN 3 O 4 Si (M + ), found 453.1500; LRMS ( EI) m / z
453 (M + ), 424, 409, 394, 352, 181, 131, 119.Example 11 (20S) -11,12-difluoro-7-trimethylsilylcamptothecin and (20S) -9,10-difluoro-7-trimethylsilyl Production of camptothecin (3: 1 mixture each)
【００７４】 [0074]
【００７５】 実施例1-(2)に記載の手順に従い、実施例1-(1)で製造した化合物(44.5 mg, 0.
10 mmol)及び2,3-ジフルオロフェニル イソニトリル [Weber, W. P. et al., Te
trahedron Lett., 13, 1637 (1972)の手順に従い、収率20%で製造し、ワークア ップ前に室温で2日間攪拌した] (42 mg, 0.30 mmol)を得、フラッシュクロマト グラフィー (CHCl3/MeOH 95:5; CHCl3/アセトン 10:1〜4:1)の後、前記の位置異
性体を含む22.6 mg (50%)のわずかに黄色の油を得た: 1H NMR (300 MHz, CDCl3 ) 0.56 (d, J = 4.8 Hz, 1 Hマイナー), 0.65 (s, 9 Hメシ゛ャー), 1.00 (t, J = 7.4 H z, 3 H), 1.86 (m, 2 H), 3.87 (br s, 1 Hマイナー), 3.97 (br s, 1 Hメシ゛ャー), 5.0
-5.47 (m, 3 H), 5.68 (d, J = 16.5 Hz, 1 H), 5.70 (d, J = 16.4 Hz, 1 Hマイナ ー ), 7.31 (m, 1 Hマイナー), 7.44 (dt, J = 9.4, 7.4 Hz, 1 Hメシ゛ャー), 7.59 (s, 1
Hマイナー), 7.60 (s, 1 Hメシ゛ャー), 7.68 (m, 1 Hマイナー), 7.93 (m, 1 Hメシ゛ャー); C23H 22 F2N2O4Si (M+) について計算したHRMS (EI) m/z 456.1317,実測値456.1321; LRMS (EI) m/z 456 (M+), 438, 428, 412, 383, 356, 327. 実施例12 20S-7-トリイソプロピルシリルカンプトテシンの製造According to the procedure described in Example 1- (2), the compound prepared in Example 1- (1) (44.5 mg, 0.2
10 mmol) and 2,3-difluorophenyl isonitrile (Weber, W.P. et al., Te
prepared in 20% yield according to the procedure of trahedron Lett., 13, 1637 (1972) and stirred at room temperature for 2 days before the work-up] (42 mg, 0.30 mmol) and obtained by flash chromatography (CHClThree/ MeOH 95: 5; CHClThree/ Acetone 10: 1-4: 1)
There were obtained 22.6 mg (50%) of a slightly yellow oil containing the following:1H NMR (300 MHz, CDClThree ) 0.56 (d, J = 4.8 Hz, 1 Hminor), 0.65 (s, 9 HMesher), 1.00 (t, J = 7.4 Hz, 3 H), 1.86 (m, 2 H), 3.87 (br s, 1 Hminor), 3.97 (br s, 1 HMesher), 5.0
-5.47 (m, 3 H), 5.68 (d, J = 16.5 Hz, 1 H), 5.70 (d, J = 16.4 Hz, 1 HMinor ー ), 7.31 (m, 1 Hminor), 7.44 (dt, J = 9.4, 7.4 Hz, 1 HMesher), 7.59 (s, 1
Hminor), 7.60 (s, 1 HMesher), 7.68 (m, 1 Hminor), 7.93 (m, 1 HMesher); Ctwenty threeH twenty two FTwoNTwoOFourSi (M+HRMS (EI) m / z 456.1317, found 456.1321; LRMS (EI) m / z 456 (M+), 438, 428, 412, 383, 356, 327.Example 12 Production of 20S-7-triisopropylsilylcamptothecin
【００７６】 [0076]
【００７７】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オキソ-7-(トリイソプロピルシリ ル-2-プロピニル)-1H-ピラノ[3,4-c]-8-ピリドン 実施例1-(1)に記載の手順に従い、ヨードピリドン 2, (200 mg, 0.598 mmol)
とトリイソプロピルシリル-2-プロピニルブロミド (329 mg, 1.196 mmol)とを組
み合わせた。クロマトグラフィー (CH2Cl2/AcOEt 9:1)により、41.1 mg (13%)の
白色のフォームを得た: 1H NMR (300 MHz, CDCl3) 0.91 (t, J = 7 Hz, 6 H)
, 0.99 (s, 18 H), 1.71 (m, J = 7 Hz, 2 H), 3.65 (s, 1 H), 5.0-5.2 (m, 3
H), 5.45 (d, J = 16 Hz, 1 H), 7.13 (s, 1 H); 13C NMR (75 MHz, CDCl3)
7.7, 11.2, 18.7, 31.7, 44.6, 66.5, 71.9, 87.7, 100.1, 116.6, 118.2, 148.
6, 158.0, 173.4; について計算したHRMS (EI) m/z C22H32INO4Si (M+) 529.116
2,実測値529.1145; LRMS (EI) m/z 529 (M+), 486, 442, 82, 59.(1) (S) -4-Ethyl-4-hydroxy-6-iodo-3-oxo-7- (triisopropylsilyl-2-propynyl) -1H-pyrano [3,4-c]- 8-Pyridone According to the procedure described in Example 1- (1), iodopyridone 2, (200 mg, 0.598 mmol)
And triisopropylsilyl-2-propynyl bromide (329 mg, 1.196 mmol). Chromatography (CH 2 Cl 2 / AcOEt 9: 1) gave 41.1 mg (13%) of a white foam: 1 H NMR (300 MHz, CDCl 3 ) 0.91 (t, J = 7 Hz, 6 H )
, 0.99 (s, 18 H), 1.71 (m, J = 7 Hz, 2 H), 3.65 (s, 1 H), 5.0-5.2 (m, 3
H), 5.45 (d, J = 16 Hz, 1 H), 7.13 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 )
7.7, 11.2, 18.7, 31.7, 44.6, 66.5, 71.9, 87.7, 100.1, 116.6, 118.2, 148.
HRMS (EI) m / z C 22 H 32 INO 4 Si (M + ) calculated for 6, 158.0, 173.4;
2, found 529.1145; LRMS (EI) m / z 529 (M + ), 486, 442, 82, 59.
【００７８】 (2) (20S)-7-トリイソプロピルシリルカンプトテシン 実施例1-(2)に記載の方法に従い、前記のピリドン(41 mg, 0.077 mmol)から23
.3 mg (60%)の明るい黄色の固体を得た: []20 D +31.7 (c 0.2, CH2Cl2); IR (CH
Cl3, cm-1) 3026, 3008, 2996, 2962, 2950, 2932, 2892, 2869, 1742, 1658, 1
598, 1555, 1466, 1230, 1220, 1158; 1H NMR (300 MHz, CDCl3) 1.02 (t, J
= 7 Hz, 3 H), 1.18 (d, J = 7 Hz, 18 H), 1.60-2.0 (m, 5 H), 2.17 (s, 1 H
), 5.31 (d, J = 16 Hz, 1 H), 5.41 (s, 2 H), 5.76 (d, J = 16, 1 H), 7.61
(t, J = 7 Hz, 1 H), 7.69 (s, 1 H), 7.78 (t, J = 7 Hz 1 H), 8.20 (t, J =
7 Hz, 2 H); 13C NMR (125 MHz, CDCl3) 7.9, 13.5, 19.2, 31.7, 52.6, 66.
5, 72.9, 98.4, 118.6, 127.1, 129.7, 130.2, 130.4, 133.6, 136.3, 145.0, 1
46.0, 150.3, 150.6, 157.4, 174.1; C29H36N2O4Si (M+) について計算したHRM
S (EI) m/z 504.2444,実測値504.2436; LRMS (EI) m/z 504 (M+), 461, 433,
419, 405, 391, 375, 361, 347, 311, 275, 174, 93, 69, 59. 実施例13 20S-7-トリイソプロピルシリルカンプトテシンの製造(2) (20S) -7-Triisopropylsilylcamptothecin According to the method described in Example 1- (2), the above pyridone (41 mg, 0.077 mmol) was converted to 23
.3 mg (60%) of a light yellow solid were obtained: [] 20 D +31.7 (c 0.2, CH 2 Cl 2 ); IR (CH
Cl 3 , cm -1 ) 3026, 3008, 2996, 2962, 2950, 2932, 2892, 2869, 1742, 1658, 1
598, 1555, 1466, 1230, 1220, 1158; 1 H NMR (300 MHz, CDCl 3 ) 1.02 (t, J
= 7 Hz, 3 H), 1.18 (d, J = 7 Hz, 18 H), 1.60-2.0 (m, 5 H), 2.17 (s, 1 H
), 5.31 (d, J = 16 Hz, 1 H), 5.41 (s, 2 H), 5.76 (d, J = 16, 1 H), 7.61
(t, J = 7 Hz, 1 H), 7.69 (s, 1 H), 7.78 (t, J = 7 Hz 1 H), 8.20 (t, J =
7 Hz, 2 H); 13 C NMR (125 MHz, CDCl 3 ) 7.9, 13.5, 19.2, 31.7, 52.6, 66.
5, 72.9, 98.4, 118.6, 127.1, 129.7, 130.2, 130.4, 133.6, 136.3, 145.0, 1
46.0, 150.3, 150.6, 157.4, 174.1; C 29 H 36 N 2 O 4 Si (M +) calculated for HRM
S (EI) m / z 504.2444, found 504.2436; LRMS (EI) m / z 504 (M + ), 461, 433,
419, 405, 391, 375, 361, 347, 311, 275, 174, 93, 69, 59.Example 13 Production of 20S-7-triisopropylsilylcamptothecin
【００７９】 [0079]
【００８０】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オキソ-7-(トリエチルシリル-2-プ
ロピニル)-1H-ピラノ[3,4-c]-8-ピリドン 実施例1-(1)に記載の手順に従い、ヨードピリドン2(150 mg, 0.450 mmol)とト
リエチルシリル-2-プロピニルブロミド (210 mg, 0.90 mmol)とを組み合わせた 。クロマトグラフィー (CH2Cl2/AcOEt 9:1)により、97.0 mg (45%)の白色のフォ
ームを得た: 1H NMR (300 MHz, CDCl3) 0.54 (q, J = 8 Hz, 6 H), 0.92 (t,
J = 8 Hz, 12 H), 1.74 (m, J = 7 Hz, 2 H), 3.57 (s, 1 H), 4.9-5.1 (m, 3
H), 5.46 (d, J = 16 Hz, 1 H), 7.13 (s, 1 H); 13C NMR (75 MHz, CDCl3)
4.1, 7.4, 7.6, 31.5, 44.5, 66.3, 71.8, 88.7, 99.2, 100.0, 116.5, 118.1,
148.5, 158.0, 173.2; C19H26INO4Si (M+) について計算したHRMS (EI) m/z 487
.0676,実測値487.0688; LRMS (EI) m/z 487 (M+), 458, 430, 420, 402, 360,
332, 153, 141, 125, 96, 83, 68, 57.(1) (S) -4-Ethyl-4-hydroxy-6-iodo-3-oxo-7- (triethylsilyl-2-propynyl) -1H-pyrano [3,4-c] -8- Pyridone According to the procedure described in Example 1- (1), iodopyridone 2 (150 mg, 0.450 mmol) and triethylsilyl-2-propynyl bromide (210 mg, 0.90 mmol) were combined. Chromatography (CH 2 Cl 2 / AcOEt 9: 1) gave 97.0 mg (45%) of a white foam: 1 H NMR (300 MHz, CDCl 3 ) 0.54 (q, J = 8 Hz, 6 H ), 0.92 (t,
J = 8 Hz, 12 H), 1.74 (m, J = 7 Hz, 2 H), 3.57 (s, 1 H), 4.9-5.1 (m, 3
H), 5.46 (d, J = 16 Hz, 1 H), 7.13 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 )
4.1, 7.4, 7.6, 31.5, 44.5, 66.3, 71.8, 88.7, 99.2, 100.0, 116.5, 118.1,
148.5, 158.0, 173.2; C 19 H 26 INO 4 Si (M +) HRMS calculated for (EI) m / z 487
.0676, found 487.0688; LRMS (EI) m / z 487 (M + ), 458, 430, 420, 402, 360,
332, 153, 141, 125, 96, 83, 68, 57.
【００８１】 (2) (20S)-7-トリエチルシリルカンプトテシン 実施例1-(2)に記載の手順に従い、前記ピリドン(48.7 mg, 0.1 mmol)より29.8
mg (65%)の明るい黄色の固体を得た: []20 D +35.9 (c 0.2, CH2Cl2); IR (CHCl 3 , cm-1) 3015, 3002, 2960, 2935, 1741, 1658, 1599, 1219, 1199, 1158; 1H
NMR (300 MHz, CDCl3) 0.80-1.00 (m, 12 H), 1.0-1.18 (m, 6 H), 1.70-1.9
0 (m, 2 H), 5.22-5.27 (m, 3 H), 5.69 (d, J = 16 Hz, 1 H), 7.58 (t, J = 7
Hz, 1 H), 7.63 (s, 1 H), 7.72 (t, J = 7 Hz 1 H), 8.18 (m, 2 H); 13C NM
R (125 MHz, CDCl3) 5.0, 7.6, 7.9, 31.7, 52.1, 66.5, 72.9, 97.7, 118.3,
127.4, 127.9, 129.7, 131.2, 132.6, 136.1, 142.6, 146.6, 147.9, 150.2, 1
50.9, 157.6, 174.1; C26H30N2O4Si (M+) について計算したHRMS (EI) m/z 462
.1975,実測値462.1982; LRMS (EI) m/z 462 (M+), 433, 418, 405, 389, 361,
256, 220, 205, 189, 178, 149, 137, 123, 109, 95, 81, 69, 57. 実施例14 (20S)-7-(ジメチル-(1エS,2エS,5エS) 7,7 ジメチルノルピニルシリル)カンプトテ シンの製造(2) (20S) -7-triethylsilylcamptothecin 29.8 g of the pyridone (48.7 mg, 0.1 mmol) according to the procedure described in Example 1- (2).
mg (65%) of a light yellow solid was obtained: []20 D +35.9 (c 0.2, CHTwoClTwo); IR (CHCl Three , cm-1) 3015, 3002, 2960, 2935, 1741, 1658, 1599, 1219, 1199, 1158;1H
NMR (300 MHz, CDClThree) 0.80-1.00 (m, 12 H), 1.0-1.18 (m, 6 H), 1.70-1.9
0 (m, 2 H), 5.22-5.27 (m, 3 H), 5.69 (d, J = 16 Hz, 1 H), 7.58 (t, J = 7
Hz, 1 H), 7.63 (s, 1 H), 7.72 (t, J = 7 Hz 1 H), 8.18 (m, 2 H);13C NM
R (125 MHz, CDClThree) 5.0, 7.6, 7.9, 31.7, 52.1, 66.5, 72.9, 97.7, 118.3,
127.4, 127.9, 129.7, 131.2, 132.6, 136.1, 142.6, 146.6, 147.9, 150.2, 1
50.9, 157.6, 174.1; C26H30NTwoOFourSi (M+HRMS (EI) m / z 462 calculated for
.1975, found 462.1982; LRMS (EI) m / z 462 (M+), 433, 418, 405, 389, 361,
256, 220, 205, 189, 178, 149, 137, 123, 109, 95, 81, 69, 57.Example 14 (20S) -7- (dimethyl- (1E, 2E, 5E) ) 7,7 Dimethylnorpinylsilyl) camptothecin
【００８２】 [0082]
【００８３】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オキソ-7-(ジメチル-(1S,2S,5S) 7
,7 ジメチルノルピニルシリル-2-プロピニル)-1H-ピラノ[3,4-c]-8-ピリドン 実施例1-(1)に記載の手順に従い、ヨードピリドン2(150 mg, 0.450 mmol)を、
ジメチル-(1S, 2S, 5S)7,7 ジメチルノルピニルシリル-2-プロピニルブロミド (
281 mg, 0.90 mmol)と組み合わせた。クロマトグラフィー (CH2Cl2/AcOEt 9:1) により、100.8 mg (39%)の白色のフォームを得た: 1H NMR (300 MHz, CDCl3)
0.10 (d, J = 2 Hz, 6 H), 0.48-0.70 (m, 2 H), 0.72 (s, 3 H), 0.93 (t, J
= 7 Hz, 3 H), 1.10 (s, 3 H), 1.15-1.40 (m, 3 H), 1.60-1.85 (m, 6 H), 1.8
8-2.00 (m, 1 H), 2.05-2.20 (m, 1 H), 3.58 (s, 1 H), 4.95 (m, 3 H), 5.46
(d, J = 16 Hz, 1 H), 7.13 (s, 1 H); 13C NMR (75 MHz, CDCl3) 0.78, 7.8
, 20.2, 23.1, 24.0, 24.8, 25.3, 27.0, 31.3, 31.7, 39.7, 40.7, 44.7, 49.1
, 66.5, 71.9, 91.0, 98.5, 100.3, 116.6, 118.3, 148.7, 158.0, 173.4.(1) (S) -4-ethyl-4-hydroxy-6-iodo-3-oxo-7- (dimethyl- (1S, 2S, 5S) 7
, 7 Dimethylnorpinylsilyl-2-propynyl) -1H-pyrano [3,4-c] -8-pyridoneIodopyridone 2 (150 mg, 0.450 mmol) To
Dimethyl- (1S, 2S, 5S) 7,7 Dimethylnorpinylsilyl-2-propynylbromide (
281 mg, 0.90 mmol). Chromatography: by (CH 2 Cl 2 / AcOEt 9 1), to give a white foam of 100.8 mg (39%): 1 H NMR (300 MHz, CDCl 3)
0.10 (d, J = 2 Hz, 6 H), 0.48-0.70 (m, 2 H), 0.72 (s, 3 H), 0.93 (t, J
= 7 Hz, 3 H), 1.10 (s, 3 H), 1.15-1.40 (m, 3 H), 1.60-1.85 (m, 6 H), 1.8
8-2.00 (m, 1 H), 2.05-2.20 (m, 1 H), 3.58 (s, 1 H), 4.95 (m, 3 H), 5.46
(d, J = 16 Hz, 1 H), 7.13 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 ) 0.78, 7.8
, 20.2, 23.1, 24.0, 24.8, 25.3, 27.0, 31.3, 31.7, 39.7, 40.7, 44.7, 49.1
, 66.5, 71.9, 91.0, 98.5, 100.3, 116.6, 118.3, 148.7, 158.0, 173.4.
【００８４】 (2) (20S)-7-(ジメチル-(1エS,2エS,5エS) 7,7 ジメチルノルピニルシリル)カンプ トテシン 実施例1-(2)に記載の手順に従い、前記ピリドン(57.0 mg, 0.1 mmol)より、29
.4 mg (54%)の明るい黄色の固体を得た: []20 D +29.2 (c 0.2, CH2Cl2); IR (CH
Cl3, cm-1) 3020, 3000, 2980, 2972, 2939, 2914, 2824, 2867, 1741, 1658, 1
599, 1556, 1264, 1231, 1201, 1157, 843; 1H NMR (300 MHz, CDCl3) 0.50-
0.70 (m, 8 H), 0.90-1.10 (m, 9 H), 1.10-1.35 (m, 4 H), 1.40-1.60 (m, 3 H
), 1.72 (m, 1 H), 1.80-1.95 (m, 2 H), 2.05-2.11 (m, 2 H), 5.25 (d, J = 1
6 Hz 1 H), 5.27 (s, 2 H), 5.69 (d, J= 16 Hz, 1 H), 7.58 (t, J= 8 Hz, 1 H
), 7.62 (s, 1 H), 7.72 (t, J= 8 Hz, 1 H), 8.10-8.2 (m, 2 H); 13C NMR (1
25 MHz, CDCl3) 1.4, 7.9, 19.9, 23.0, 24.6, 25.3, 26.8, 31.6, 31.7, 39.
6, 40.5, 49.3, 52.0, 66.5, 72.9, 97.7, 118.3, 127.3, 128.3, 129.7, 131.2
, 132.1, 134.6, 144.6, 146.6, 148.0, 150.2, 150.9, 157.6, 174.0; C32H38 N2O4Si (M+) について計算したHRMS (EI) m/z 542.2601,実測値542.2588; LRMS
(EI) m/z 542 (M+), 498, 487, 460, 443, 431, 406, 387, 377, 362, 333, 3
18, 304, 289, 275, 219, 178, 166, 141, 115, 95, 67. 実施例15 (20S)-7-(3-シアノプロピルジメチルシリル)カンプトテシン(2) (20S) -7- (dimethyl- (1E, 2E, 5E) 7,7 dimethylnorpinylsilyl) camptothecin The procedure described in Example 1- (2) According to the pyridone (57.0 mg, 0.1 mmol), 29
.4 mg (54%) of a light yellow solid were obtained: [] 20 D +29.2 (c 0.2, CH 2 Cl 2 ); IR (CH
Cl 3 , cm -1 ) 3020, 3000, 2980, 2972, 2939, 2914, 2824, 2867, 1741, 1658, 1
599, 1556, 1264, 1231, 1201, 1157, 843; 1 H NMR (300 MHz, CDCl 3 ) 0.50-
0.70 (m, 8 H), 0.90-1.10 (m, 9 H), 1.10-1.35 (m, 4 H), 1.40-1.60 (m, 3 H
), 1.72 (m, 1 H), 1.80-1.95 (m, 2 H), 2.05-2.11 (m, 2 H), 5.25 (d, J = 1
6 Hz 1 H), 5.27 (s, 2 H), 5.69 (d, J = 16 Hz, 1 H), 7.58 (t, J = 8 Hz, 1 H
), 7.62 (s, 1 H), 7.72 (t, J = 8 Hz, 1 H), 8.10-8.2 (m, 2 H); 13 C NMR (1
25 MHz, CDCl 3 ) 1.4, 7.9, 19.9, 23.0, 24.6, 25.3, 26.8, 31.6, 31.7, 39.
6, 40.5, 49.3, 52.0, 66.5, 72.9, 97.7, 118.3, 127.3, 128.3, 129.7, 131.2
, 132.1, 134.6, 144.6, 146.6 , 148.0, 150.2, 150.9, 157.6, 174.0; C 32 H 38 N 2 O 4 Si (M +) for calculated HRMS (EI) m / z 542.2601 , Found 542.2588; LRMS
(EI) m / z 542 (M + ), 498, 487, 460, 443, 431, 406, 387, 377, 362, 333, 3
18, 304, 289, 275, 219, 178, 166, 141, 115, 95, 67.Example 15 (20S) -7- (3-cyanopropyldimethylsilyl) camptothecin
【００８５】 [0085]
【００８６】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード-3-オキソ-7-(3-シアノプロピルジメ チルシリル-2-プロピニル)-1H-ピラノ[3,4-c]-8-ピリドン Ricoら(J. Org. Chem. 1994, 59, 415)により引用される手順に従い、ヨード ピリドン2(150 mg, 0.450 mmol)を、3-シアノプロピルジメチルシリル-2-プロピ
ニルブロミド (165 mg, 0.678 mmol)、K2CO3 (124 mg, 0.90 mmol)、Bu4N+Br- (
14.5 mg, 0.045 mmol)、H2O (0.02 mL)及びトルエン (3.6 mL)と組み合わせた。
この混合物を1時間還流した。ろ過及びクロマトグラフィー (CH2Cl2/AcOEt 9:1)
の後、34.0 mg (15%)の白色の油を得た: 1H NMR (300 MHz, CDCl3) 0.17 (s,
6 H), 0.70-0.80 (m, 2 H), 0.98 (t, J = 7 Hz, 3 H), 1.70-1.90 (m, 4 H),
2.39 (t, J = 7, 2 H), 3.66 (s, 1 H), 4.9-5.22 (m, 3 H), 5.51 (d, J = 16
Hz, 1 H), 7.19 (s, 1 H); 13C NMR (125 MHz, CDCl3) -2.1, 7.8, 15.4, 20
.5, 20.6, 31.6, 44.6, 66.4, 71.9, 89.1, 99.6, 100.0, 116.7, 118.3, 119.7
, 148.8, 158.0, 173.3; C19H23IN2O4Si (M+) について計算したHRMS (EI) m/z
498.0472,実測値498.0480; LRMS (EI) m/z 498 (M+), 483, 470, 445, 430, 4
16, 402, 392, 371, 348, 335, 306, 290, 266, 223, 202, 185, 163, 136, 126
, 109, 98, 81, 69, 57.(1) (S) -4-Ethyl-4-hydroxy-6-iodo-3-oxo-7- (3-cyanopropyldimethylsilyl-2-propynyl) -1H-pyrano [3,4-c ] -8-Pyridone Following the procedure cited by Rico et al. (J. Org. Chem. 1994, 59, 415), iodopyridone 2 (150 mg, 0.450 mmol) was (165 mg, 0.678 mmol), K 2 CO 3 (124 mg, 0.90 mmol), Bu 4 N + Br - (
14.5 mg, 0.045 mmol), was combined with H 2 O (0.02 mL) and toluene (3.6 mL).
The mixture was refluxed for 1 hour. Filtration and chromatography (CH 2 Cl 2 / AcOEt 9: 1)
After 34.0 mg (15%) of a white oil were obtained: 1 H NMR (300 MHz, CDCl 3 ) 0.17 (s,
6 H), 0.70-0.80 (m, 2 H), 0.98 (t, J = 7 Hz, 3 H), 1.70-1.90 (m, 4 H),
2.39 (t, J = 7, 2 H), 3.66 (s, 1 H), 4.9-5.22 (m, 3 H), 5.51 (d, J = 16
Hz, 1 H), 7.19 (s, 1 H); 13 C NMR (125 MHz, CDCl 3 ) -2.1, 7.8, 15.4, 20
.5, 20.6, 31.6, 44.6, 66.4, 71.9, 89.1, 99.6, 100.0, 116.7, 118.3, 119.7
, 148.8, 158.0, 173.3; HRMS (EI) m / z calculated for C 19 H 23 IN 2 O 4 Si (M + )
498.0472, found 498.0480; LRMS (EI) m / z 498 (M + ), 483, 470, 445, 430, 4
16, 402, 392, 371, 348, 335, 306, 290, 266, 223, 202, 185, 163, 136, 126
, 109, 98, 81, 69, 57.
【００８７】 (2) (20S)-7-(3-シアノプロピルジメチルシリル)カンプトテシン 実施例1-(2)に記載の手順に従い、前記のピリドン(25.0 mg, 0.05 mmol)より 、9.8 mg (41%)の明るい黄色の固体を得た: []20 D +34.3 (c 0.2, CH2Cl2); IR
(CHCl3, cm-1) 3025, 3016, 1741, 1659, 1600, 1264, 1222; 1H NMR (300 MHz
, CDCl3) 0.71 (s, 6 H), 1.05 (t, J = 7 Hz,3 H), 1.26 (m, 2 H),1.66 (m,
2H), 1.90 (m, 2 H), 2.35 (t, J = 7 Hz, 2 H), 3.76 (s, 1 H), 5.31 (d, J
= 16 Hz, 1 H), 5.31 (s, 2 H), 5.75 (d, J = 16 Hz, 1 H), 7.67 (m, 2 H), 7
.82 (t, J = 8 Hz, 1 H), 8.17 (d, J = 8 Hz 1 H), 8.24 (d, J = 8 Hz, 1 H);
13C NMR (125 MHz, CDCl3) 0.2, 7.9, 16.8, 20.7, 20.73, 31.7, 50.9, 66
.5, 72.8, 97.9, 118.5, 119.2, 127.7, 127.8, 130.0, 131.4, 131.9, 135.2,
141.9, 146.3, 148.1, 150.3, 151.1, 157.5, 174.0; C26H27N3O4Si (M+) につ
いて計算したHRMS (EI) m/z 473.1771,実測値473.1755; LRMS (EI) m/z 473 (
M+), 444, 429, 414, 400, 389, 373 362, 344, 331, 303, 289, 2.75, 245, 21
9, 166, 152, 130, 98, 71. 実施例16 (20S)-7-(3-ハロプロピルジメチルシリル)カンプトテシンの製造(2) (20S) -7- (3-cyanopropyldimethylsilyl) camptothecin According to the procedure described in Example 1- (2), 9.8 mg (41 mmol) was obtained from the aforementioned pyridone (25.0 mg, 0.05 mmol). %) Of a bright yellow solid: [] 20 D +34.3 (c 0.2, CH 2 Cl 2 ); IR
(CHCl 3 , cm -1 ) 3025, 3016, 1741, 1659, 1600, 1264, 1222; 1 H NMR (300 MHz
, CDCl 3 ) 0.71 (s, 6 H), 1.05 (t, J = 7 Hz, 3 H), 1.26 (m, 2 H), 1.66 (m,
2H), 1.90 (m, 2 H), 2.35 (t, J = 7 Hz, 2 H), 3.76 (s, 1 H), 5.31 (d, J
= 16 Hz, 1 H), 5.31 (s, 2 H), 5.75 (d, J = 16 Hz, 1 H), 7.67 (m, 2 H), 7
.82 (t, J = 8 Hz, 1 H), 8.17 (d, J = 8 Hz 1 H), 8.24 (d, J = 8 Hz, 1 H);
13 C NMR (125 MHz, CDCl 3 ) 0.2, 7.9, 16.8, 20.7, 20.73, 31.7, 50.9, 66
.5, 72.8, 97.9, 118.5, 119.2, 127.7, 127.8, 130.0, 131.4, 131.9, 135.2,
141.9, 146.3, 148.1, 150.3, 151.1, 157.5, 174.0; C 26 H 27 N 3 O 4 Si (M +) for calculated HRMS (EI) m / z 473.1771 , Found 473.1755; LRMS (EI) m / z 473 (
M + ), 444, 429, 414, 400, 389, 373 362, 344, 331, 303, 289, 2.75, 245, 21
9, 166, 152, 130, 98, 71. Example 16 Production of (20S) -7- (3-halopropyldimethylsilyl) camptothecin
【００８８】 [0088]
【００８９】 (1) (S)-4-エチル-4-ヒドロキシ-6-ヨード(及び6-ブロモ)-3-オキソ-7-(3-クロ ロプロピルジメチルシリル-2-プロピニル)-1H-ピラノ[3,4-c]-8-ピリドン 実施例1-(1)に記載の手順に従い、[ヨードピリドン 2 (150 mg, 0.450 mmol)
と3-クロロプロピルジメチルシリル-2-プロピニルブロミド (228 mg, 0.90 mmol
)とを組み合わせた。クロマトグラフィー (CH2Cl2/AcOEt 9:1)により、75.4 mg
(33%)の透明な油を得た。NMR分析は、アルキルブロミド、更には所望のクロロ誘
導体の存在を前者有利に1．6：1の割合で示した: 1H NMR (300 MHz, CDCl3)
0.09 (s, 6 H), 0.60-0.70 (m, 2 H), 0.85-0.89 (t, J = 7 Hz, 3 H), 1.60-1.
95 (m, 4 H), 3.33 (t, J= 7 Hz, 2 H,ヨードに割り当てられる), 3.44 (t, J =
7 Hz, 2 H,ブロモに割り当てられる), 3.75 (s, 1 H), 4.91-5.18 (m, 3 H), 5
.42 (d, J= 16 Hz, 1 H), 7.12 (s, 1 H).(1) (S) -4-ethyl-4-hydroxy-6-iodo (and 6-bromo) -3-oxo-7- (3-chloropropyldimethylsilyl-2-propynyl) -1H- Pyrano [3,4-c] -8-pyridone According to the procedure described in Example 1- (1), [iodopyridone 2 (150 mg, 0.450 mmol)
And 3-chloropropyldimethylsilyl-2-propynyl bromide (228 mg, 0.90 mmol
). 75.4 mg by chromatography (CH 2 Cl 2 / AcOEt 9: 1)
(33%) of a clear oil was obtained. NMR analysis showed the presence of the alkyl bromide and also the desired chloro derivative in the former advantageously in a ratio of 1.6: 1: 1 H NMR (300 MHz, CDCl 3 ).
0.09 (s, 6 H), 0.60-0.70 (m, 2 H), 0.85-0.89 (t, J = 7 Hz, 3 H), 1.60-1.
95 (m, 4 H), 3.33 (assigned to t, J = 7 Hz, 2 H, iodine), 3.44 (t, J =
7 Hz, 2 H, assigned to bromo), 3.75 (s, 1 H), 4.91-5.18 (m, 3 H), 5
.42 (d, J = 16 Hz, 1 H), 7.12 (s, 1 H).
【００９０】 (2) (20S)-7-(3-ハロプロピルジメチルシリル)カンプトテシン 実施例1-(2)に記載の手順に従い、前記のピリドン(51 mg, 0.1 mmol)により、
23 mg (49%)の明るい黄色の固体を得た。スペクトルデータの分析により、この 固体を、クロロ、ブロモ及びヨード誘導体（1．6：1：1．3）の3成分混合物とし
て同定した: []20 D +30.8 (c 0.2, CH2Cl2); IR (CHCl3, cm-1) 3029, 3012, 29
80, 2963, 2933, 1742, 1658, 1600, 1556, 1258, 1233, 1218, 1200, 1158, 10
45, 843, 822, 794; 1H NMR (300 MHz, CDCl3) 0.69 (s, 6 H), 1.04 (t, J
= 7 Hz, 3 H), 1.18-1.30 (m, 2 H), 1.60-2.0 (m, 4 H), 3.15 (t, J= 7 Hz, 2
H,ヨードに割り当てられる), 3.36 (t, J= 7 Hz, 2 H,ブロモに割り当てられる
), 3.48 (t, J = 7 Hz, 2 H, クロロに割り当てられる), 3.88 (s, 1 H), 5.30
(d, J = 16 Hz, 1 H), 5.31 (s, 2 H), 5.74 (d, J = 16 Hz, 1 H), 7.62-7.66
(m, 2 H), 7.87 (t, J = 8 Hz, 1 H), 8.18 (d, J = 8 Hz, 1 H), 8.22 (d, J =
8 Hz, 1 H); 13C NMR (125 MHz, CDCl3) 0.2, 7.9, 14.7, 27.5, 31.7, 47.
4, 51.9, 66.4, 72.8, 98.2, 118.6, 127.7, 127.9, 130.0, 131.0, 132.0, 135
.2, 146.1, 147.6, 150.2, 157.5, 174.0; C25H27ClN2O4Si (M+) について計算
したHRMS (EI) m/z 482.1429,実測値482.1413; LRMS (EI) m/z 482 (M+), 453
, 438, 361, 305, 275. 実施例17 (20S)10-アセトキシ-7-tert-ブチルジメチルシリルカンプトテシンの製造(2) (20S) -7- (3-halopropyldimethylsilyl) camptothecin According to the procedure described in Example 1- (2), the pyridone (51 mg, 0.1 mmol)
23 mg (49%) of a light yellow solid were obtained. Analysis of the spectral data identified this solid as a ternary mixture of chloro, bromo and iodo derivatives (1.6: 1: 1.3): [] 20 D +30.8 (c 0.2, CH 2 Cl 2 ) ; IR (CHCl 3 , cm -1 ) 3029, 3012, 29
80, 2963, 2933, 1742, 1658, 1600, 1556, 1258, 1233, 1218, 1200, 1158, 10
45, 843, 822, 794; 1 H NMR (300 MHz, CDCl 3 ) 0.69 (s, 6 H), 1.04 (t, J
= 7 Hz, 3 H), 1.18-1.30 (m, 2 H), 1.60-2.0 (m, 4 H), 3.15 (t, J = 7 Hz, 2
H, assigned to iodine), 3.36 (t, J = 7 Hz, 2 H, assigned to bromo
), 3.48 (assigned to t, J = 7 Hz, 2 H, chloro), 3.88 (s, 1 H), 5.30
(d, J = 16 Hz, 1 H), 5.31 (s, 2 H), 5.74 (d, J = 16 Hz, 1 H), 7.62-7.66
(m, 2 H), 7.87 (t, J = 8 Hz, 1 H), 8.18 (d, J = 8 Hz, 1 H), 8.22 (d, J =
8 Hz, 1 H); 13 C NMR (125 MHz, CDCl 3 ) 0.2, 7.9, 14.7, 27.5, 31.7, 47.
4, 51.9, 66.4, 72.8, 98.2, 118.6, 127.7, 127.9, 130.0, 131.0, 132.0, 135
.2, 146.1, 147.6, 150.2, 157.5, 174.0; C 25 H 27 ClN 2 O 4 Si (M +) for calculated HRMS (EI) m / z 482.1429 , Found 482.1413; LRMS (EI) m / z 482 (M + ), 453
, 438, 361, 305, 275. Example 17 Production of (20S) 10-acetoxy-7-tert-butyldimethylsilylcamptothecin
【００９１】 [0091]
【００９２】 実施例1-(2)に記載の手順に従い、前記ピリドン(34.5 mg, 0.071 mmol)及びp-
アセトキシイソニトリルより、21.3 mg (58%)の明るい黄色の固体を得た: []20 D +36.2 (c 0.2, CH2Cl2); IR (CHCl3, cm-1) 3029, 3000, 2958, 2931, 2902, 2
885, 2859, 1742, 1659, 1600, 1557, 1504, 1464, 1371, 1256, 1232, 1195, 1
166, 1045; 1H NMR (300 MHz, CDCl3) 0.69 (s, 6 H), 0.90 (s, 9 H), 1.04
(t, J = 7 Hz, 3 H), 1.80-2.00 (m, J = 7 Hz, 2 H), 2.40 (s, 3 H), 3.81 (
s, 1 H), 5.30 (d, J = 16 Hz 1 H), 5.31.(s, 2 H), 5.75 (d, J = 16 Hz, 1 H
), 7.53 (dd, J 1= 9 Hz, J 2= 2 Hz, 1 H), 7.65 (s, 1 H), 8.08 (d, J = 2 H
z, 1 H), 8.21 (d, J = 9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) 0.6, 7.9, 1
9.3, 21.5, 27.2, 31.7, 52.5, 66.5, 72.9, 97.7, 118.4, 120.4, 124.8, 132.
1, 133.2, 136.7, 142.8, 146.2, 146.4, 149.0, 150.2, 150.8, 157.5, 169.1,
174.1; LRMS (EI) m/z 520 (M+), 478, 463, 421, 377, 347, 320, 291, 57.According to the procedure described in Example 1- (2), the pyridone (34.5 mg, 0.071 mmol) and p-
Acetoxyisonitrile gave 21.3 mg (58%) of a bright yellow solid: [] 20 D +36.2 (c 0.2, CH 2 Cl 2 ); IR (CHCl 3 , cm -1 ) 3029, 3000, 2958, 2931, 2902, 2
885, 2859, 1742, 1659, 1600, 1557, 1504, 1464, 1371, 1256, 1232, 1195, 1
166, 1045; 1 H NMR (300 MHz, CDCl 3 ) 0.69 (s, 6 H), 0.90 (s, 9 H), 1.04
(t, J = 7 Hz, 3 H), 1.80-2.00 (m, J = 7 Hz, 2 H), 2.40 (s, 3 H), 3.81 (
s, 1 H), 5.30 (d, J = 16 Hz 1 H), 5.31. (s, 2 H), 5.75 (d, J = 16 Hz, 1 H
), 7.53 (dd, J 1 = 9 Hz, J 2 = 2 Hz, 1 H), 7.65 (s, 1 H), 8.08 (d, J = 2 H
z, 1 H), 8.21 (d, J = 9 Hz, 1 H); 13 C NMR (125 MHz, CDCl 3 ) 0.6, 7.9, 1
9.3, 21.5, 27.2, 31.7, 52.5, 66.5, 72.9, 97.7, 118.4, 120.4, 124.8, 132.
1, 133.2, 136.7, 142.8, 146.2, 146.4, 149.0, 150.2, 150.8, 157.5, 169.1,
174.1; LRMS (EI) m / z 520 (M + ), 478, 463, 421, 377, 347, 320, 291, 57.
【００９３】 実施例18 (2) (20S)10-アセトキシ-7-tert-ブチルジメチルシリルカンプトテシン 実施例2-(2)に記載の手順に従い、前記ピリドン(34.5 mg, 0.071 mmol)より、
同一のクロマトグラフィー条件を使用して、21.3 mg (58%)の明るい黄色の固体 を得た: []20 D +36.2 (c 0.2, CH2Cl2); IR (CHCl3, cm-1) 3029, 3000, 2958,
2931, 2902, 2885, 2859, 1742, 1659, 1600, 1557, 1504, 1464, 1371, 1256,
1232, 1195, 1166, 1045; 1H NMR (300 MHz, CDCl3) 0.69 (s, 6 H), 0.90 (s
, 9 H), 1.04 (t, J = 7 Hz, 3 H), 1.80- 2.00 (m, J = 7 Hz, 2 H), 2.40 (s,
3 H), 3.81 (s, 1 H), 5.30 (d, J = 16 Hz 1 H), 5.31.(s, 2 H), 5.75 (d, J
= 16 Hz, 1 H), 7.53 (dd, J 1= 9 Hz, J 2= 2 Hz, 1 H), 7.65 (s, 1 H), 8.0
8 (d, J = 2 Hz, 1 H), 8.21 (d, J = 9 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
0.6, 7.9, 19.3, 21.5, 27.2, 31.7, 52.5, 66.5, 72.9, 97.7, 118.4, 120.4
, 124.8, 132.1, 133.2, 136.7, 142.8, 146.2, 146.4, 149.0, 150.2, 150.8,
157.5, 169.1, 174.1; C28H32N2O6Si (M+) について計算したHRMS (EI) m/z 52
0.2030,実測値520.2014 LRMS (EI) m/z 520 (M+), 478, 463, 421, 377, 347,
320, 291, 57. 実施例19Example 18 (2) (20S) 10-acetoxy-7-tert-butyldimethylsilylcamptothecin According to the procedure described in Example 2- (2), the pyridone (34.5 mg, 0.071 mmol)
Using the same chromatography conditions, 21.3 mg (58%) of a bright yellow solid were obtained: [] 20 D +36.2 (c 0.2, CH 2 Cl 2 ); IR (CHCl 3 , cm −1 ) 3029, 3000, 2958,
2931, 2902, 2885, 2859, 1742, 1659, 1600, 1557, 1504, 1464, 1371, 1256,
1232, 1195, 1166, 1045; 1 H NMR (300 MHz, CDCl 3 ) 0.69 (s, 6 H), 0.90 (s
, 9 H), 1.04 (t, J = 7 Hz, 3 H), 1.80-2.00 (m, J = 7 Hz, 2 H), 2.40 (s,
3 H), 3.81 (s, 1 H), 5.30 (d, J = 16 Hz 1 H), 5.31. (S, 2 H), 5.75 (d, J
= 16 Hz, 1 H), 7.53 (dd, J 1 = 9 Hz, J 2 = 2 Hz, 1 H), 7.65 (s, 1 H), 8.0
8 (d, J = 2 Hz, 1 H), 8.21 (d, J = 9 Hz, 1 H); 13 C NMR (125 MHz, CDCl 3 )
0.6, 7.9, 19.3, 21.5, 27.2, 31.7, 52.5, 66.5, 72.9, 97.7, 118.4, 120.4
, 124.8, 132.1, 133.2, 136.7, 142.8, 146.2, 146.4, 149.0, 150.2, 150.8,
157.5, 169.1, 174.1; C 28 H 32 N 2 O 6 Si (M +) for calculated HRMS (EI) m / z 52
0.2030, Found 520.2014 LRMS (EI) m / z 520 (M + ), 478, 463, 421, 377, 347,
320, 291, 57. Example 19
【００９４】 [0094]
【００９５】 (20S)10-ヒドロキシ-7-tert-ブチルジメチルシリルカンプトテシン 実施例5に記載の手順に従い、実施例18に記載の化合物(13.4 mg, 0.026 mmol)
をヒドロキシ誘導体に変換した。分離用TLCプレート上における精製(2:1 CH2Cl2 :アセトン)により、10.6 mg (85%)の黄色の固体を得た: []20 D +17.4 (c 0.2, 3
:1 CH2Cl2/MeOH); 1H NMR (300 MHz, 3:1 CDCl3/CD3OD) 0.66 (s, 6 H), 0.88
-1.05 (m, 12 H), 1.80- 2.00 (m, 2 H), 5.25-5.30 (m, 3 H), 5.70 (d, J = 1
6 Hz, 1 H), 7.37 (dd, J 1= 9 Hz, J 2= 2 Hz, 1 H), 7.54 (d, J = 2 Hz, 1 H
), 7.60 (s, 1 H), 8.05 (d, J = 9 Hz, 1 H); 13C NMR (125 MHz, (3:1) CDCl 3 :CD3OD) 8.1, 20.6, 27.6, 30.4, 31.9, 53.6, 66.5, 73.9, 98.6, 112.1, 11
8.8, 123.3, 132.1, 135.6, 137.4, 141.6, 143.8, 147.3, 148.4, 152.6, 157.
5, 158.7, 174.7; C26H30N2O5Si (M+) について計算したHRMS (EI) m/z 478.19
24,実測値478.1947 LRMS (EI) m/z 478 (M+), 434, 421, 377, 304, 284, 227,
178, 149, 137, 109, 97, 83, 69, 57. 本発明を、前記の実施例と結びつけて詳細に記載したけれども、このような詳
細な記載は単にその目的のためだけであり、添付の請求の範囲により限定される
ことを除いて本発明の精神から離れることなく当業者は改変を行うことができる
ことを理解すべきである(20S) 10-Hydroxy-7-tert-butyldimethylsilylcamptothecin Following the procedure described in Example 5, the compound described in Example 18 (13.4 mg, 0.026 mmol)
Was converted to the hydroxy derivative. Purification on separation TLC plate (2: 1 CHTwoClTwo : Acetone) gave 10.6 mg (85%) of a yellow solid: []20 D +17.4 (c 0.2, 3
: 1 CHTwoClTwo/ MeOH);1H NMR (300 MHz, 3: 1 CDClThree/ CDThreeOD) 0.66 (s, 6 H), 0.88
-1.05 (m, 12 H), 1.80- 2.00 (m, 2 H), 5.25-5.30 (m, 3 H), 5.70 (d, J = 1
6 Hz, 1 H), 7.37 (dd, J 1 = 9 Hz, J 2 = 2 Hz, 1 H), 7.54 (d, J = 2 Hz, 1 H
), 7.60 (s, 1 H), 8.05 (d, J = 9 Hz, 1 H);13C NMR (125 MHz, (3: 1) CDCl Three : CDThreeOD) 8.1, 20.6, 27.6, 30.4, 31.9, 53.6, 66.5, 73.9, 98.6, 112.1, 11
8.8, 123.3, 132.1, 135.6, 137.4, 141.6, 143.8, 147.3, 148.4, 152.6, 157.
5, 158.7, 174.7; C26H30NTwoOFiveSi (M+HRMS (EI) m / z 478.19 calculated for
24, measured 478.1947 LRMS (EI) m / z 478 (M+), 434, 421, 377, 304, 284, 227,
178, 149, 137, 109, 97, 83, 69, 57. Although the present invention has been described in detail in connection with the above embodiments, such details have been described.
The detailed description is merely for that purpose and is limited by the appended claims.
A person skilled in the art can make modifications without departing from the spirit of the invention except that
Should understand that
【図１】 式１の化合物の調製に関する一般合成スキームの図である。1 is a diagram of a general synthetic scheme for the preparation of compounds of Formula 1.
【図２】 (20S)-11-フルオロ-7-トリメチルシリルカンプトテシンの合成の図である。FIG. 2 is a diagram of the synthesis of (20S) -11-fluoro-7-trimethylsilylcamptothecin.
【図３】 (20S)-10-アセトキシ-7-トリメチルシリルカンプトテシン及び(20S)-10-ヒド ロキシ-7-トリメチルシリルカンプトテシンの合成の図である。FIG. 3 is a diagram of the synthesis of (20S) -10-acetoxy-7-trimethylsilylcamptothecin and (20S) -10-hydroxy-7-trimethylsilylcamptothecin.
【図４】 (20S)-10-アミノ-7-トリメチルシリルカンプトテシンの合成の図である。FIG. 4 is a diagram of the synthesis of (20S) -10-amino-7-trimethylsilylcamptothecin.
【図５】 (20S)-10-アミノ-11-フルオロ-7-トリメチルシリルカンプトテシンの合成の図
である。FIG. 5 is a diagram of the synthesis of (20S) -10-amino-11-fluoro-7-trimethylsilylcamptothecin.
【図６】 イリノテカンの新規類似体の合成の図である。FIG. 6 is a diagram of the synthesis of a novel analog of irinotecan.
───────────────────────────────────────────────────── フロントページの続き (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＧＷ，ＭＬ， ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＧＭ，Ｋ Ｅ，ＬＳ，ＭＷ，ＳＤ，ＳＺ，ＵＧ，ＺＷ)，ＥＡ(ＡＭ ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ，ＲＵ，ＴＪ，ＴＭ) ，ＡＬ，ＡＭ，ＡＴ，ＡＵ，ＡＺ，ＢＡ，ＢＢ，ＢＧ， ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ，ＣＵ，ＣＺ，ＤＥ，Ｄ Ｋ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＥ，ＧＨ，ＧＭ，ＨＲ ，ＨＵ，ＩＤ，ＩＬ，ＩＳ，ＪＰ，ＫＥ，ＫＧ，ＫＰ， ＫＲ，ＫＺ，ＬＣ，ＬＫ，ＬＲ，ＬＳ，ＬＴ，ＬＵ，Ｌ Ｖ，ＭＤ，ＭＧ，ＭＫ，ＭＮ，ＭＷ，ＭＸ，ＮＯ，ＮＺ ，ＰＬ，ＰＴ，ＲＯ，ＲＵ，ＳＤ，ＳＥ，ＳＧ，ＳＩ， ＳＫ，ＳＬ，ＴＪ，ＴＭ，ＴＲ，ＴＴ，ＵＡ，ＵＧ，Ｕ Ｚ，ＶＮ，ＹＵ，ＺＷ (72)発明者 ボム ディヴィッド アメリカ合衆国 ペンシルヴァニア州 15217 ピッツバーグ ミラー ストリー ト 885 Ｆターム(参考） 4C086 AA01 AA03 DA44 MA01 MA04 NA14 ZB26 4H049 VN01 VP01 VQ60 VR24 VS13 VU06 VU07 VW02 ──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Bomb David United States of America Pennsylvania 15217 Pittsburgh Miller Street 885 F-term (reference) 4C086 AA01 AA03 DA44 MA01 MA04 NA14 ZB26 4H049 VN01 VP01 VQ60 VR24 VS13 VU06 VU07 VW02
Claims (14)
、アルキニル基、アルコキシル基、アリールオキシ基、アシルオキシ基、カルボ
ニルオキシ基、カルバモイルオキシ基、ハロゲン、ヒドロキシル基、ニトロ基、
シアノ基、アジド基、ホルミル基、ヒドラジノ基、アシル基、アミノ基、-SRc（
式中、Rcは水素、アシル基、アルキル基、又はアリール基である）であり、又は
R1及びR2は一緒になって式-O(CH2)nO-（式中、ｎは整数１又は２を表す）の基を
形成し、 R3はＨ、Ｆ、ハロゲン原子、ニトロ基、アミノ基、ヒドロキシル基、又はシア
ノ基であり、又はR2及びR3は一緒になって式-O(CH2)nO-（式中、ｎは整数１又は
２を表す）の基を形成し、 R4はＨ、Ｆ、C1-3アルキル基、C2-3アルケニル基、C2-3アルキニル基、又はC1 -3 アルコキシル基であり、 R5はC1-10アルキル基、又はプロパルギル基であり、かつ R6、R7及びR8は独立にC1-10アルキル基、C2-10アルケニル基、C2-10アルキニ ル基、アリール基又は-(CH2)NR9基（式中、Ｎは１〜10の範囲内の整数であり、 かつR9はヒドロキシル基、アルコキシ基、アミノ基、アルキルアミノ基、ジアル
キルアミノ基、ハロゲン原子、シアノ基又はニトロ基である）である）1. Structure: And a pharmaceutically acceptable salt thereof. (Wherein, R 1 and R 2 are independently the same or different, and include hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, a carbonyloxy group, a carbamoyloxy group, a halogen, Hydroxyl group, nitro group,
Cyano, azide, formyl, hydrazino, acyl, amino, -SR c
Wherein R c is hydrogen, an acyl group, an alkyl group, or an aryl group), or
R 1 and R 2 together form a group of the formula —O (CH 2 ) n O—, wherein n represents an integer 1 or 2, and R 3 is H, F, a halogen atom, a nitro A group, an amino group, a hydroxyl group, or a cyano group, or R 2 and R 3 together form a group of the formula —O (CH 2 ) n O—, wherein n represents an integer 1 or 2. forming a, R 4 is H, F, a C 1-3 alkyl group, C 2-3 alkenyl, C 2-3 alkynyl, or C 1 -3 alkoxy group, R 5 is C 1-10 alkyl Or a propargyl group, and R 6 , R 7 and R 8 are independently a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, an aryl group or-(CH 2 ) N R 9 groups (wherein N is an integer in the range of 1 to 10, and R 9 is a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group Is))
ル基、ハロゲン、アミノ基、ニトロ基、シアノ基、C1-3アルキル基、C2-3アルケ
ニル基、C2-3アルキニル基又はC1-3アルコキシル基である請求の範囲第１項記載
の化合物。3. R 1 and R 2 are independently the same or different, and are H, hydroxyl, halogen, amino, nitro, cyano, C 1-3 alkyl, C 2-3 alkenyl, The compound according to claim 1, which is a C 2-3 alkynyl group or a C 1-3 alkoxyl group.
ルキル基、C1-3アミノアルキル基、C1-3アルキルアミノ基又はC1-3ジアルキルア
ミノ基である請求の範囲第１項記載の化合物。4. The method according to claim 1, wherein R 1 and R 2 are independently the same or different, and each is selected from a C 1-3 perhaloalkyl group, a C 1-3 aminoalkyl group, a C 1-3 alkylamino group and a C 1-3 dialkylamino. 2. The compound according to claim 1, which is a group.
アミノ基、ニトロ基、シアノ基、又はヒドロキシル基である請求の範囲第１項記
載の化合物。5. R 1 and R 2 are independently the same or different, H, methyl group,
The compound according to claim 1, which is an amino group, a nitro group, a cyano group, or a hydroxyl group.
、ジメチルアミノ基、エチルアミノ基、ジエチルアミノ基、ヒドロキシメチル基
、アミノメチル基、メチルアミノメチル基、又はジメチルアミノメチル基である
請求の範囲第１項記載の化合物。6. R 1 and R 2 are independently the same or different and each is a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a hydroxymethyl group, an aminomethyl group, a methylaminomethyl group, or a dimethyl group. The compound according to claim 1, which is an aminomethyl group.
１項記載の化合物。7. The compound according to claim 1, wherein R 3 is F, an amino group, or a hydroxyl group.
ル基、フェニル基又は-(CH2)NR9基（式中、Ｎは１〜６の範囲内の整数であり、 かつR9はヒドロキシル基、アルコキシ基、アミノ基、アルキルアミノ基、ジアル
キルアミノ基、ハロゲン原子、シアノ基又はニトロ基である）である請求の範囲
第１項記載の化合物。9. R 6 , R 7 and R 8 are independently the same or different and each is a C 1-6 alkyl group, a phenyl group or a — (CH 2 ) N R 9 group, wherein N is 1 to And R 9 is a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group. Compound.
合物。10. The compound according to claim 1, wherein R 6 , R 7 and R 8 are a methyl group.
シ基を形成する請求の範囲第１項記載の化合物。11. The compound according to claim 1, wherein R 2 and R 3 form a methylenedioxy group or a 1,2-ethylenedioxy group.
ルシリル-10-アセトキシカンプトテシン、7-トリメチルシリル-10-ヒドロキシカ
ンプトテシン、7-トリメチルシリル-11-フルオロカンプトテシン、7-トリメチル
シリル-9-フルオロカンプトテシン、7-トリメチルシリル-10-フルオロカンプト テシン、7-トリメチルシリル-10-アミノカンプトテシン、7-トリメチルシリル-1
1-アミノカンプトテシン、7-トリメチルシリル-11,12-ジフルオロカンプトテシ ン、7-トリメチルシリル-9,10-ジフルオロカンプトテシン、7-トリメチルシリル
-10-アミノ-11-フルオロカンプトテシン、7-tert-ブチルジメチルシリルカンプ トテシン、7-tert-ブチルジメチルシリル-10-アセトキシカンプトテシン、7-ter
t-ブチルジメチルシリル-10-ヒドロキシカンプトテシン、7-ジメチル-3-シアノ プロピルシリルカンプトテシン、7-ジメチル-3-ハロプロピルシリルカンプトテ シン、7-トリフェニルシリルカンプトテシン、7-トリエチルシリルカンプトテシ
ン、7-ジメチルノルピニルシリルカンプトテシンである請求の範囲第１項記載の
化合物。13. The compound according to claim 7, wherein the compound is 7-trimethylsilylcamptothecin, 7-trimethylsilyl-10-acetoxycamptothecin, 7-trimethylsilyl-10-hydroxycamptothecin, 7-trimethylsilyl-11-fluorocamptothecin, 7-trimethylsilyl-9-fluorocamptothecin, 7-trimethylsilyl-9-fluorocamptothecin Trimethylsilyl-10-fluorocamptothecin, 7-trimethylsilyl-10-aminocamptothecin, 7-trimethylsilyl-1
1-aminocamptothecin, 7-trimethylsilyl-11,12-difluorocamptothecin, 7-trimethylsilyl-9,10-difluorocamptothecin, 7-trimethylsilyl
-10-amino-11-fluorocamptothecin, 7-tert-butyldimethylsilylcamptothecin, 7-tert-butyldimethylsilyl-10-acetoxycamptothecin, 7-ter
t-butyldimethylsilyl-10-hydroxycamptothecin, 7-dimethyl-3-cyanopropylsilylcamptothecin, 7-dimethyl-3-halopropylsilylcamptothecin, 7-triphenylsilylcamptothecin, 7-triethylsilylcamptothecin, 7- 2. The compound according to claim 1, which is dimethylnorpinylsilylcamptothecin.
上許される塩を投与する工程を含むことを特徴とする患者の治療方法。14. A method for treating a patient, comprising the step of administering a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/921,102 US6150343A (en) | 1993-06-30 | 1997-08-29 | Camptothecin analogs and methods of preparation thereof |
| US08/921,102 | 1997-08-29 | ||
| PCT/US1998/017683 WO1999009996A1 (en) | 1997-08-29 | 1998-08-26 | Camptothecin analogs and methods of preparation thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2001513567A true JP2001513567A (en) | 2001-09-04 |
| JP2001513567A5 JP2001513567A5 (en) | 2006-01-05 |
| JP4903936B2 JP4903936B2 (en) | 2012-03-28 |
Family
ID=25444921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000507386A Expired - Fee Related JP4903936B2 (en) | 1997-08-29 | 1998-08-26 | Camptothecin analogs and methods for their preparation |
Country Status (9)
| Country | Link |
|---|---|
| US (6) | US6150343A (en) |
| EP (1) | EP1017399B1 (en) |
| JP (1) | JP4903936B2 (en) |
| AT (1) | ATE418338T1 (en) |
| AU (1) | AU760543B2 (en) |
| CA (1) | CA2302226C (en) |
| DE (1) | DE69840388D1 (en) |
| ES (1) | ES2320183T3 (en) |
| WO (1) | WO1999009996A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002532505A (en) * | 1998-12-15 | 2002-10-02 | ユニヴァーシティ オブ ピッツバーグ | Camptothecin analogs and methods for their preparation |
| JP2011500674A (en) * | 2007-10-16 | 2011-01-06 | バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド | C10-substituted camptothecin analogs |
| JP2011500675A (en) * | 2007-10-16 | 2011-01-06 | バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド | C7-substituted camptothecin analogs |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6150343A (en) * | 1993-06-30 | 2000-11-21 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
| US6743917B2 (en) | 1993-06-30 | 2004-06-01 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
| FR2754179B1 (en) | 1996-10-08 | 1998-12-24 | Theramex | NOVEL HORMONONAL COMPOSITION AND ITS USE |
| US6207832B1 (en) * | 1999-04-09 | 2001-03-27 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
| WO2002062340A1 (en) * | 2001-02-07 | 2002-08-15 | University Of Kentucky Research Foundation | Highly lipophilic camptothecin prodrugs, methods of preparation, and formulations thereof |
| US6372906B1 (en) * | 2001-04-12 | 2002-04-16 | University Of Pittsburgh | Synthesis of silyl camptothecins and silyl homocamptothecins |
| US6723853B2 (en) | 2001-08-27 | 2004-04-20 | University Of Pittsburgh | Intermediates and methods of preparation of intermediates in the enantiomeric synthesis of (20R)homocamptothecins and the enantiomeric synthesis of (20R)homocamptothecins |
| AU2003239538A1 (en) * | 2002-05-22 | 2003-12-12 | University Of Pittsburgh | Synthesis of polycyclic quinolines |
| CA2548543C (en) | 2003-12-17 | 2012-01-03 | Bionumerik Pharmaceuticals, Inc. | Process for making camptothecin derivatives |
| US7346153B2 (en) * | 2004-11-12 | 2008-03-18 | International Business Machines Corporation | Dynamically alerting callers of changes to menu structures in a telephone prompting system |
| PE20080145A1 (en) * | 2006-03-21 | 2008-02-11 | Janssen Pharmaceutica Nv | TETRAHYDRO-PYRIMIDOAZEPINE AS MODULATORS OF TRPV1 |
| EP1998809B1 (en) | 2006-03-30 | 2014-06-25 | Drais Pharmaceuticals, Inc. | Camptothecin-cell penetrating peptide conjugates and pharmaceutical compositions containing the same |
| JP5562865B2 (en) | 2007-12-17 | 2014-07-30 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | TRPV1 imidazolo-, oxazolo-, and thiazolopyrimidine modulators |
| WO2016064900A1 (en) * | 2014-10-22 | 2016-04-28 | Arno Therapeutics, Inc. | Methods and systems for camptothecin analog synthesis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001511807A (en) * | 1997-02-14 | 2001-08-14 | バイオニューメリック・ファーマスーティカルズ，インコーポレイテッド | Highly lipophilic camptothecin derivative |
| JP2002532505A (en) * | 1998-12-15 | 2002-10-02 | ユニヴァーシティ オブ ピッツバーグ | Camptothecin analogs and methods for their preparation |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5405963A (en) * | 1993-06-10 | 1995-04-11 | Smithkline Beecham Corporation | Process for asymmetric total synthesis of camptothecin analogues |
| US5744605A (en) | 1993-06-30 | 1998-04-28 | University Of Pittsburgh | Intermediates in the synthesis of (+) camptothecin and related compounds and synthesis thereof |
| US6211371B1 (en) | 1993-06-30 | 2001-04-03 | University Of Pittsburgh | Intermediates in the synthesis of camptothecin and related compounds and synthesis thereof |
| US6743917B2 (en) * | 1993-06-30 | 2004-06-01 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
| US6252079B1 (en) | 1993-06-30 | 2001-06-26 | University Of Pittsburgh | Intermediates in the synthesis of camptothecin and related compounds and synthesis thereof |
| US6150343A (en) * | 1993-06-30 | 2000-11-21 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
| BR9711319B1 (en) * | 1996-08-19 | 2009-08-11 | highly lipophilic camptothecin derivatives. | |
| US6169080B1 (en) * | 1997-02-13 | 2001-01-02 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic camptothecin derivatives |
| US6948279B1 (en) | 1997-04-22 | 2005-09-27 | Caldwell Manufacturing Company | Support system for laterally removable sash |
| US6057303A (en) * | 1998-10-20 | 2000-05-02 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic Camptothecin derivatives |
| US6403604B1 (en) * | 2001-03-01 | 2002-06-11 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
| US7687497B2 (en) * | 2007-10-16 | 2010-03-30 | Bionumerik Pharmaceuticals, Inc. | C10-substituted camptothecin analogs |
-
1997
- 1997-08-29 US US08/921,102 patent/US6150343A/en not_active Expired - Lifetime
-
1998
- 1998-08-26 AT AT98944535T patent/ATE418338T1/en active
- 1998-08-26 ES ES98944535T patent/ES2320183T3/en not_active Expired - Lifetime
- 1998-08-26 AU AU92056/98A patent/AU760543B2/en not_active Ceased
- 1998-08-26 JP JP2000507386A patent/JP4903936B2/en not_active Expired - Fee Related
- 1998-08-26 WO PCT/US1998/017683 patent/WO1999009996A1/en active IP Right Grant
- 1998-08-26 DE DE69840388T patent/DE69840388D1/en not_active Expired - Lifetime
- 1998-08-26 EP EP98944535A patent/EP1017399B1/en not_active Expired - Lifetime
- 1998-08-26 CA CA2302226A patent/CA2302226C/en not_active Expired - Fee Related
-
2000
- 2000-08-07 US US09/633,561 patent/US6455699B1/en not_active Expired - Lifetime
-
2002
- 2002-09-20 US US10/251,153 patent/US20030105324A1/en not_active Abandoned
-
2003
- 2003-07-29 US US10/629,432 patent/US7271159B2/en not_active Expired - Fee Related
-
2007
- 2007-07-09 US US11/825,729 patent/US7514418B2/en not_active Expired - Fee Related
- 2007-10-31 US US11/981,059 patent/US7655640B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001511807A (en) * | 1997-02-14 | 2001-08-14 | バイオニューメリック・ファーマスーティカルズ，インコーポレイテッド | Highly lipophilic camptothecin derivative |
| JP2002532505A (en) * | 1998-12-15 | 2002-10-02 | ユニヴァーシティ オブ ピッツバーグ | Camptothecin analogs and methods for their preparation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002532505A (en) * | 1998-12-15 | 2002-10-02 | ユニヴァーシティ オブ ピッツバーグ | Camptothecin analogs and methods for their preparation |
| JP2011500674A (en) * | 2007-10-16 | 2011-01-06 | バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド | C10-substituted camptothecin analogs |
| JP2011500675A (en) * | 2007-10-16 | 2011-01-06 | バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド | C7-substituted camptothecin analogs |
Also Published As
| Publication number | Publication date |
|---|---|
| US20040029835A1 (en) | 2004-02-12 |
| US7271159B2 (en) | 2007-09-18 |
| ATE418338T1 (en) | 2009-01-15 |
| US7655640B2 (en) | 2010-02-02 |
| US6455699B1 (en) | 2002-09-24 |
| CA2302226C (en) | 2010-08-24 |
| EP1017399A4 (en) | 2002-11-13 |
| DE69840388D1 (en) | 2009-02-05 |
| US20030105324A1 (en) | 2003-06-05 |
| US20070259905A1 (en) | 2007-11-08 |
| US7514418B2 (en) | 2009-04-07 |
| AU9205698A (en) | 1999-03-16 |
| JP4903936B2 (en) | 2012-03-28 |
| AU760543B2 (en) | 2003-05-15 |
| CA2302226A1 (en) | 1999-03-04 |
| WO1999009996A1 (en) | 1999-03-04 |
| EP1017399B1 (en) | 2008-12-24 |
| US6150343A (en) | 2000-11-21 |
| US20080269169A1 (en) | 2008-10-30 |
| ES2320183T3 (en) | 2009-05-19 |
| EP1017399A1 (en) | 2000-07-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7514418B2 (en) | Camptothecin analogs and methods of preparation thereof | |
| JP4638987B2 (en) | Camptothecin analogs and methods for their preparation | |
| JPWO2020178282A5 (en) | ||
| CZ299794B6 (en) | Camptothecin analogs, process of their preparation and pharmaceutical compositions in which the analogs are comprised | |
| EP4265620A1 (en) | Novel camptothecin derivative, composition containing same, and use thereof | |
| CN116813631A (en) | Camptothecins compound and conjugate thereof | |
| JP2024520283A (en) | Chemical coupling linkers and uses thereof | |
| JP4923067B2 (en) | Camptothecin derivatives and their applications | |
| US6743917B2 (en) | Camptothecin analogs and methods of preparation thereof | |
| KR100706566B1 (en) | Pentacyclic taxane compounds | |
| EP2197879B1 (en) | C7-substituted camptothecin analogs | |
| US7687496B2 (en) | C7-substituted camptothecin analogs | |
| Versace | The silatecans, a novel class of lipophilic camptothecins | |
| EP1480984A2 (en) | Condensed camptothecins as antitumor agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050825 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050825 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090413 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20090713 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20090721 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091013 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100812 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20101112 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20101119 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20101210 |
|
| RD13 | Notification of appointment of power of sub attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7433 Effective date: 20110304 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20110304 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110428 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110502 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20110609 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20110908 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20110915 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20111005 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20111013 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20111109 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20111208 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20120106 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150113 Year of fee payment: 3 |
|
| LAPS | Cancellation because of no payment of annual fees |